Expanding ACMG variant classification guidelines into a general framework

Table 5 “Gold-standard” LoF variants in SPINK1

Variant		gpAF in gnomAD^a	hspAF in gnomAD^a
Nucleotide change	Amino acid change	gpAF in gnomAD^a	hspAF in gnomAD^a
Presumed complete functional loss
c.-28,211_*2,066del		Absent
c.-15,969_*7,702del		Absent
c.-320_c.55 + 961del		Absent
c.2 T > G	p.Met1?	Absent
c.2 T > C	p.Met1?	Absent
c.27delC	p.Ser10ValfsTer5	0.00001197	0.00002896 (Latino/Admixed American)
c.55 + 1G > A		Absent
c.87 + 1G > A		Absent
c.98_99insA	p.Tyr33Ter	Absent
c.177delG	p.Val60TyrfsTer35	Absent
c.194 + 1G > A		Absent
Experimentally demonstrated complete or almost complete functional loss
c.41T > C	p.Leu14Pro	Absent
c.41T > G	p.Leu14Arg	Absent
c.123G > C	p.Lys41Asn^b	Absent
c.143G > A	p.Gly48Glu	Absent
c.150T > G	p.Asp50Glu	0.000003991	0.000008834 (non-Finnish European)
c.160T > C	p.Tyr54His	Absent
c.190A > G	p.Asn64Asp	Absent
c.198A > C	p.Lys66Asn	0.0002272	0.0004129 (non-Finnish European)
c.199C > T	p.Arg67Cys	Absent
c.200G > A	p.Arg67His^c	0.003187	0.03078 (African/African American)
c.206C > T	p.Thr69Ile	0.00001198	0.0001635 (East Asian)
c.236G > T	p.Cys79Phe	Absent
c.14_c.15ins359		Absent

See the Genetic Risk Factors in Chronic Pancreatitis Database [38] for original genetic and functional analysis reports
gpAF global population allele frequency, hspAF highest subpopulation allele frequency, LoF loss-of-function
^aIn accordance with gnomAD v2.1.1 or SVs v2.1 (https://gnomad.broadinstitute.org/) [74]
^bFunctional analysis of this variant was performed in ref. [66]
^cThis variant was regarded as an outlier and was therefore excluded from the final analysis

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