Variant classification summary

NM_001379610.1:c.101A>G

SPINK1 · NP_001366539.1:p.(Asn34Ser) · NM_001379610.1

GRCh37: chr5:147207678 T>C · GRCh38: chr5:147828115 T>C

Gene: SPINK1 Transcript: NM_001379610.1

Final call

Likely Benign

PS4 strong BS3 supporting BP4 supporting

Variant details

Gene

SPINK1

Transcript

NM_001379610.1

Protein

NP_001366539.1:p.(Asn34Ser)

gnomAD AF

0.011044636179973435 (v4.1)

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Benign: PS4 strong alone does not satisfy a generic pathogenic combination rule.

2

Likely Benign: BS3 supporting shows unchanged recombinant N34S trypsin-inhibitory function with no increased susceptibility.

3

Likely Benign: BP4 supporting is met because REVEL 0.199 is below the 0.29 threshold.

Final determination: Under the generic ACMG/AMP 2015 fallback, two supporting benign criteria (BS3 supporting and BP4 supporting) satisfy the Likely Benign rule, while PS4 strong alone does not satisfy a pathogenic rule.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no documented pathogenic alternate-nucleotide variant producing the same p.Asn34Ser change was available for comparison.	clinvar
PS2	Not assessed	Not assessed: no documented de novo result with confirmed maternity and paternity, disease-affected proband, and absent family history.
PS3	Not assessed	Not assessed: the variant-specific study reports recurrent-pancreatitis association (OR 19.1) but provides no damaging functional assay.	PMID:19888199
PS4	Met	Met: pancreatitis cases had 9.1% versus 0.7% controls, yielding OR 13.38 (95% CI 7.09-25.24), above the >5.0 threshold with the interval excluding 1.0.	PMID:12483248 PMID:19888199 PMID:19453252
PM1	Not met	Not met: residue 34 has no documented statistically significant hotspot or established critical-domain designation in the available evidence.	hotspots cosmic
PM2	Not met	Not met: gnomAD v4.1 AF=0.0110446, far above the PM2 threshold of 0.0001.	gnomad_v4 gnomad_v2
PM3	Not assessed	Not assessed: no affected-proband observation establishes SPINK1 c.101A>G in trans with a pathogenic variant through parental or offspring phase testing.	PMID:19888199 PMID:19453252 PMID:12483248
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no verified pathogenic different-missense comparator at SPINK1 residue 34 was identified.	pm5_candidates clinvar
PM6	Not assessed	Not assessed: no clinical report supports assumed de novo occurrence without parental maternity and paternity confirmation.
PP1	Not assessed	Not assessed: no affected relatives or variant-positive affected family members are reported, so no informative meioses are available.	PMID:19888199
PP2	Not assessed	Not assessed: gene-wide evidence for both low benign missense variation and a common missense disease mechanism is unavailable.	PMID:19453252 PMID:12483248 gnomad_v4
PP3	Not met	Not met: missense REVEL score 0.199 is below the PP3 supporting threshold of 0.644.	revel
PP4	Not assessed	Not assessed: no patient-specific phenotype or family history is provided to test the PP4 requirement for a highly specific single-etiology disease.
PP5	Not met	Not met: ClinVar has no exact-variant expert-panel Pathogenic or Likely pathogenic classification, only conflicting ordinary laboratory submissions.	clinvar
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF=0.0204286, below the BA1 threshold of 0.05.	gnomad_v4 gnomad_v2 PMID:19453252 PMID:19888199
BS1	Not assessed	Not assessed: grpmax FAF=0.0204286 exceeds 0.01, but prevalence, penetrance, and allelic-heterogeneity inputs for a maximum-credible frequency are unavailable.	gnomad_v4 gnomad_v2 PMID:19453252 PMID:19888199
BS2	Not met	Not met: gnomAD v4.1 reports 131 homozygotes, but SPINK1 N34S has intermediate penetrance and healthy-adult status is not established.	gnomad_v4 gnomad_v2 PMID:19453252 PMID:19888199
BS3	Met	Met at supporting: recombinant N34S retained wild-type trypsin inhibition across pH and calcium conditions with no increased trypsin susceptibility.	PMID:12483248
BS4	Not assessed	Not assessed: no affected relatives tested negative for the variant, and no familial non-segregation observation is documented.	PMID:19888199
BP1	Not assessed	Not assessed: the available evidence does not establish that SPINK1 disease is primarily caused by truncating variants.	pvs1_gene_context PMID:19453252
BP2	Not assessed	Not assessed: no evidence establishes c.101A>G in trans or cis with a pathogenic variant in an affected individual or family.	PMID:19888199 PMID:19453252 PMID:12483248
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met, supporting: missense REVEL score 0.199 is below the BP4 supporting threshold of 0.29.	revel
BP5	Not assessed	Not assessed: no individual case is documented with this variant plus a confirmed alternate molecular basis for the disease.
BP6	Not met	Not met: the only Likely benign ClinVar assertion is from a single laboratory, with no exact-variant expert-panel Benign or Likely benign classification.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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