NM_006180.4:c.1937G>A

NTRK2 · NP_006171.2:p.(Arg646Lys) · NM_006180.4

GRCh37: chr9:87563549 G>A · GRCh38: chr9:84948634 G>A

Gene: NTRK2 Transcript: NM_006180.4

Final call

VUS

PM2 supporting PP3 supporting

Variant details

Gene

NTRK2

Transcript

NM_006180.4

Protein

NP_006171.2:p.(Arg646Lys)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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.

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.

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).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	PVS1 is reserved for null variants (nonsense, frameshift, canonical ±1,2 splice sites). NM_006180.4:c.1937G>A is a missense variant (p.Arg646Lys) and does not fall into any PVS1 null-variant bucket per ClinGen SVI recommendations (PMC6185798).	pvs1_generic_framework
PS1	Not met	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.	clinvar
PS2	Not met	No de novo observation has been reported for NM_006180.4:c.1937G>A in the literature or public databases.
PS3	Not met	No variant-specific functional studies have been published for NM_006180.4:c.1937G>A (p.Arg646Lys). OncoKB classifies this variant as 'Unknown Oncogenic Effect' with no reviewed functional evidence. No systematic functional characterization of the surrounding region exists in the literature.	oncokb
PS4	Not met	No case-control studies or statistical enrichment data exist for NM_006180.4:c.1937G>A in affected individuals versus controls.
PS5	Not met	No reputable source (e.g., clinical diagnostic laboratory) has reported NM_006180.4:c.1937G>A as pathogenic in the absence of accessible evidence. The variant is absent from ClinVar.	clinvar
PM1	Not met	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.	oncokb
PM2	Met	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%).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No pathogenic missense variant at the same amino acid residue (Arg646) has been reported in ClinVar or the literature. The PM5 candidate search returned zero same-residue comparator variants.	pm5_candidates clinvar
PM6	Not met	No de novo observation (with or without confirmed maternity/paternity) has been reported for NM_006180.4:c.1937G>A.
PP1	Not met	No co-segregation data are available for NM_006180.4:c.1937G>A; no family studies have been reported.
PP2	Not met	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. No gnomAD missense constraint data were available for NTRK2 in the evidence packet, precluding application of PP2.
PP3	Met	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 spliceai bayesdel
PP4	Not met	No patient phenotype or family history data are available for this case. PP4 requires a phenotype highly specific for the gene/disease, which cannot be assessed without clinical context.
PP5	Not met	No reputable source has reported NM_006180.4:c.1937G>A as pathogenic. The variant is absent from ClinVar.	clinvar
BA1	Not met	NM_006180.4:c.1937G>A is absent from all population databases (gnomAD v2.1, v4.1, gnomAD-Canada). BA1 requires an allele frequency >5%.	gnomad_v2 gnomad_v4
BS1	Not met	NM_006180.4:c.1937G>A is absent from population databases. BS1 requires an allele frequency greater than expected for the disorder (>0.3% under generic ACMG).	gnomad_v2 gnomad_v4
BS2	Not met	No observation of NM_006180.4:c.1937G>A in a healthy adult has been reported for a fully penetrant disorder. The variant is absent from population databases.
BS3	Not met	No functional studies demonstrating a benign effect for NM_006180.4:c.1937G>A have been published. OncoKB reports no variant-specific functional evidence.	oncokb
BS4	Not met	No segregation data are available for NM_006180.4:c.1937G>A. BS4 requires lack of segregation in affected family members, which cannot be assessed without family-based genotype data.
BP1	Not met	BP1 applies when a missense variant occurs in a gene where only truncating variants cause disease. While NTRK2 loss-of-function is supported as a disease mechanism, missense variants have also been implicated in germline disease (e.g., kinase-domain missense variants reported in developmental disorders), so a truncating-only mechanism cannot be assumed.	pvs1_gene_context
BP2	Not met	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	Not met	Multiple in silico predictors suggest a deleterious effect rather than a benign effect. REVEL score is 0.776 (pathogenic range) and SpliceAI predicts splice alteration (max delta = 0.53). BP4 requires multiple lines of computational evidence suggesting no impact, which is contradicted by the observed scores.	revel spliceai bayesdel
BP5	Not met	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	Not met	No reputable source has reported NM_006180.4:c.1937G>A as benign. The variant is absent from ClinVar.	clinvar
BP7	N/A	BP7 applies to synonymous variants predicted to have no splice impact. NM_006180.4:c.1937G>A is a missense variant (p.Arg646Lys), not a synonymous variant.

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