Variant classification summary

NM_001370466.1:c.2938dup

NOD2 · NP_001357395.1:p.(Leu980ProfsTer2) · NM_001370466.1

GRCh37: chr16:50763778 G>GC · GRCh38: chr16:50729867 G>GC

Gene: NOD2 Transcript: NM_001370466.1

Final call

Pathogenic

PVS1 strong PS4 strong

Variant details

Gene

NOD2

Transcript

NM_001370466.1

Protein

NP_001357395.1:p.(Leu980ProfsTer2)

gnomAD AF

0.01813616036836422 (v4.1)

ClinVar

Uncertain significance

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PVS1 strong reflects the NOD2 p.(L980Pfs*2) loss-of-function frameshift after the NMD-escape downgrade.

2

Pathogenic: PS4 strong reflects a homozygous Crohn disease genotype relative risk of 42.1 with a confidence interval excluding 1.

Final determination: Under the generic ACMG/AMP 2015 fallback, two strong pathogenic criteria (PVS1 strong and PS4 strong) support a Pathogenic classification.

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	Met	Met at strong: the p.(L980Pfs*2) frameshift has a stop 32 nucleotides before the exon-11/exon-12 junction, triggering the NMD-escape downgrade.	pvs1_generic_framework PMID:25741868
PS1	N/A	Not applicable: PS1 requires a missense variant, and this is a frameshift variant.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no documented de novo occurrence with confirmed maternity and paternity is available for NM_001370466.1:c.2938dup.
PS3	Not assessed	Not assessed: available functional assays studied different NOD2 variants, and no direct validated assay result for c.2938dup (p.(Leu980ProfsTer2)) was identified.	PMID:11425413 PMID:12673278 PMID:15024686 PMID:22684479
PS4	Met	Met: homozygous genotype relative risk 42.1 with 95% CI 4.3–infinity exceeds the PS4 >5 threshold and excludes 1 in Crohn disease cases versus controls.	PMID:11425413 clinvar gnomad_v4
PM1	N/A	Not applicable: PM1 requires a missense variant, and this is a frameshift variant.	generic_acmg_combination_rules
PM2	Not met	Not met: observed control frequencies are 0.0146597–0.0181362, far above the <=0.0001 PM2 threshold.	gnomad_v2 gnomad_v4 PMID:25741868
PM3	Not assessed	Not assessed: no parent or offspring testing establishes c.2938dup in trans with a pathogenic allele in a recessive disorder.
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a frameshift variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: PM5 requires a missense variant, and this is a frameshift variant.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no apparently de novo occurrence without confirmed maternity and paternity is documented for this variant.
PP1	Not assessed	Not assessed: zero informative affected-relative meioses or exact-variant segregation results are documented for NM_001370466.1:c.2938dup.	PMID:12673278 PMID:15024686
PP2	N/A	Not applicable: PP2 requires a missense variant, and this is a frameshift variant.	generic_acmg_combination_rules
PP3	N/A	Not applicable: c.2938dup is a frameshift (p.L980Pfs*2), outside PP3's missense or intronic/splice-region scope.	spliceai
PP4	Not assessed	Not assessed: the patient's phenotype and family history are insufficient to establish a highly specific phenotype for a single genetic etiology.
PP5	Not met	Not met: ClinVar reports zero expert-panel submissions, so conflicting laboratory and aggregate classifications cannot trigger PP5.	clinvar
BA1	Not met	Not met: required grpmax FAF values are 0.02141027–0.0239652, all below the 0.05 BA1 threshold.	gnomad_v2 gnomad_v4 PMID:25741868
BS1	Not assessed	Not assessed: grpmax FAF is 0.02141027, but reduced/incomplete penetrance and missing maximum-credible-frequency inputs prevent using the 1% default alone.	gnomad_v2 gnomad_v4 PMID:25741868
BS2	Not assessed	Not assessed: gnomAD reports 28–607 homozygotes, but healthy-adult status and full early-age penetrance are not established.	gnomad_v2 gnomad_v4 PMID:25741868
BS3	Not assessed	Not assessed: no direct validated assay showed normal protein function or splicing for NOD2 c.2938dup (p.(Leu980ProfsTer2)).	PMID:11425413 PMID:12673278 PMID:15024686 PMID:22684479
BS4	Not assessed	Not assessed: no affected relatives with documented genotypes are available to demonstrate lack of segregation for this variant.
BP1	N/A	Not applicable: BP1 requires a missense variant, and this is a frameshift variant.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no family-level phase data show c.2938dup in trans with a dominant pathogenic allele or in cis with any pathogenic allele.
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a frameshift variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	N/A	Not applicable: c.2938dup is a frameshift (p.L980Pfs*2), so SpliceAI max delta 0.055 cannot support BP4.	spliceai
BP5	Not assessed	Not assessed: no patient-level evidence identifies an alternate molecular basis for the disease in a case carrying this variant.
BP6	Not met	Not met: ClinVar reports zero expert-panel submissions, so ordinary laboratory benign assertions cannot trigger BP6.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a frameshift variant.	generic_acmg_combination_rules

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