Classification rationale

PM2PP3 VUS

NTRK2 c.1937G>A

NM_006180.4:c.1937G>A (p.Arg646Lys) is a missense variant in the NTRK2 kinase domain (exon 18). It is absent from all large population cohorts (gnomAD v2.1, v4.1, gnomAD-Canada), meeting PM2 at supporting level.¹ Multiple in silico tools predict a deleterious effect: REVEL score 0.776 (pathogenic range), SpliceAI max delta 0.53 with a predicted donor gain, and BayesDel 0.27, meeting PP3 at supporting level.² No variant-specific functional studies, de novo observations, segregation data, or ClinVar classifications exist for this variant. The variant has not been reported in the literature.³ Under generic ACMG/AMP 2015 combination rules: PM2_Supporting + PP3_Supporting = one supporting pathogenic criterion. This does not reach the threshold for Likely Pathogenic (requires ≥2 supporting or ≥1 moderate). The variant is classified as a Variant of Uncertain Significance (VUS).⁴

PM2 + PP3 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

2 revelspliceai ↗bayesdel

3 clinvar ↗oncokb ↗

4 generic_acmg_combination_rules

Gene diagram · NM_006180.4 · variants mapped to exon structure

NTRK2 NM_006180.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 21 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

NM_006180.4:c.1937G>A is absent from all large population cohorts, including gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. This satisfies PM2 at supporting level under generic ACMG/AMP (allele frequency <0.1%).

Absent from gnomAD v2.1 (0 alleles).Absent from gnomAD v4.1 (0 alleles).Absent from gnomAD-Canada v1.0 (0 alleles).

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

PP3 supporting Pathogenic

Multiple in silico predictors support a deleterious effect for NM_006180.4:c.1937G>A. REVEL score is 0.776 (pathogenic range, >0.5). SpliceAI predicts a cryptic donor gain (max delta score = 0.53, DS_DG = 0.53) suggesting potential splice alteration. BayesDel score is 0.27 (borderline damaging). The convergent prediction from independent tools supports PP3 at supporting level.

REVEL score 0.776 (predicted pathogenic).SpliceAI max delta score 0.53donor gain prediction (DS_DG = 0.53

spliceai ↗

Assessed · not applied

Pathogenic

PS1 No established pathogenic variant with the same amino acid change (p.Arg646Lys) arising from a different nucleotide substitution was identified in ClinVar or the literature.

PS2 No de novo observation has been reported for NM_006180.4:c.1937G>A in the literature or public databases.

PS3 No variant-specific functional studies have been published for NM_006180.4:c.1937G>A (p.Arg646Lys).

PS4 No case-control studies or statistical enrichment data exist for NM_006180.4:c.1937G>A in affected individuals versus controls.

PM1 Although p.Arg646Lys resides within the NTRK2 kinase domain, no residue-specific mutational hotspot has been identified at this position (cancerhotspots.org negative), and no variant-specific functional or clinical evidence establishes this as a critical functional domain residue for germline disease.

PM5 No pathogenic missense variant at the same amino acid residue (Arg646) has been reported in ClinVar or the literature.

PM6 No de novo observation (with or without confirmed maternity/paternity) has been reported for NM_006180.4:c.1937G>A.

PP1 No co-segregation data are available for NM_006180.4:c.1937G>A; no family studies have been reported.

PP2 PP2 requires a gene with a low rate of benign missense variation (high missense constraint z-score) where missense variants are an established mechanism of disease.

PP4 No patient phenotype or family history data are available for this case.

PP5 No reputable source has reported NM_006180.4:c.1937G>A as pathogenic.

Benign

BA1 NM_006180.4:c.1937G>A is absent from all population databases (gnomAD v2.1, v4.1, gnomAD-Canada).

BS1 NM_006180.4:c.1937G>A is absent from population databases.

BS2 No observation of NM_006180.4:c.1937G>A in a healthy adult has been reported for a fully penetrant disorder.

BS3 No functional studies demonstrating a benign effect for NM_006180.4:c.1937G>A have been published.

BS4 No segregation data are available for NM_006180.4:c.1937G>A.

BP1 BP1 applies when a missense variant occurs in a gene where only truncating variants cause disease.

BP2 No observation of NM_006180.4:c.1937G>A in trans with a known pathogenic variant has been reported for a fully penetrant disorder.

BP4 Multiple in silico predictors suggest a deleterious effect rather than a benign effect.

BP5 No case has been reported in which NM_006180.4:c.1937G>A was found in an individual with an alternate molecular basis for disease.

BP6 No reputable source has reported NM_006180.4:c.1937G>A as benign.

N/A · 2 PVS1 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.53). REVEL score = 0.776. BayesDel score = 0.269805.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. NTRK2, a receptor tyrosine kinase, is altered by mutation or chromosomal rearrangement in a diverse range of cancers.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots