NM_006180.4:c.2061C>A

NTRK2 · NP_006171.2:p.(His687Gln) · NM_006180.4

GRCh37: chr9:87570321 C>A · GRCh38: chr9:84955406 C>A

Gene: NTRK2 Transcript: NM_006180.4

Final call

VUS

PM2 moderate

Variant details

Gene

NTRK2

Transcript

NM_006180.4

Protein

NP_006171.2:p.(His687Gln)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_006180.4:c.2061C>A (p.His687Gln) is a missense variant in exon 19 of NTRK2. It is absent from all population databases (gnomAD v2.1, v4.1, gnomAD-Canada), meeting PM2.

No functional studies, case reports, segregation data, de novo observations, or ClinVar classifications are available for this variant. No publications specifically mention NM_006180.4:c.2061C>A.

Computational predictors are discordant: REVEL score 0.77 supports a deleterious effect, but BayesDel score 0.307 is borderline and does not provide a second concordant predictor to meet PP3. SpliceAI predicts no splicing impact (max delta = 0.00).

With only PM2 (moderate) met, the evidence is insufficient to classify this variant as likely pathogenic or pathogenic under the ACMG/AMP 2015 framework (PMID:25741868). 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 loss-of-function (null) variants per ClinGen SVI recommendations (PMC6185798). NM_006180.4:c.2061C>A is a missense substitution (p.His687Gln) in exon 19 and does not fall into any null-variant bucket (nonsense, frameshift, canonical ±1,2 splice, initiation codon, or exon deletion).	pvs1_generic_framework
PS1	Not met	No evidence of an established pathogenic variant with the same amino acid change (p.His687Gln) arising from a different nucleotide substitution. No ClinVar entries exist for any variant at this residue.	clinvar
PS2	Not met	No de novo observations (with maternity and paternity confirmed) have been reported for this variant. No family-based studies or trio data are available.
PS3	Not met	No variant-specific functional studies are available. OncoKB classifies this variant as 'Unknown Oncogenic Effect' and reports no reviewed functional evidence. No published functional data for NM_006180.4:c.2061C>A were identified.	oncokb
PS4	Not met	No case-control studies or proband enrichment data are available. The variant has not been reported in affected individuals.	clinvar gnomad_v2 gnomad_v4
PS5	N/A	PS5 is not part of the standard ACMG/AMP 2015 criteria (PMID:25741868). No equivalent evidence tier applies.
PM1	Not met	While p.His687 lies within the NTRK2 tyrosine kinase domain (a well-established functional domain), the variant does not reside in a statistically significant mutational hotspot. No domain-level PM1 rule exists for NTRK2 under generic ACMG, and benign variation data for the domain are unavailable.
PM2	Met	NM_006180.4:c.2061C>A is absent from all population databases including gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, consistent with a rare variant. Allele frequency is well below the 0.1% PM2 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No pathogenic missense variants have been identified at the same amino acid residue (p.His687). Automated PM5 candidate harvesting found zero same-residue comparator variants in ClinVar.	pm5_candidates clinvar
PM6	Not met	No assumed de novo observations (without maternity/paternity confirmation) have been reported for this variant.
PP1	Not met	No cosegregation data in affected families are available for this variant.
PP2	Not met	Insufficient evidence to establish that NTRK2 has a low rate of benign missense variation. No HCI prior score is available, and no gene-level constraint data for missense variation were identified.
PP3	Not met	REVEL score 0.77 exceeds the 0.5 threshold and supports a deleterious effect, but BayesDel score 0.307 is borderline and does not provide a concordant strong pathogenic prediction. A single in silico predictor does not satisfy the 'multiple lines of computational evidence' requirement for PP3 under generic ACMG/AMP.	revel bayesdel spliceai
PP4	Not met	No patient phenotype data are available. Assessment of phenotypic specificity for a single genetic etiology cannot be performed.
PP5	N/A	PP5 is not part of the standard ACMG/AMP 2015 criteria (PMID:25741868). The variant is absent from ClinVar; no reputable source reports it as pathogenic.	clinvar
BA1	Not met	Allele frequency does not exceed 1% in any population database. The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Allele frequency does not exceed 0.3% in any population database. The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	The variant has not been observed in healthy adults. No observations exist in any population database, precluding assessment of occurrence in healthy individuals despite expected full penetrance at an early age.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established functional studies demonstrating no deleterious effect are available. No functional assays have been performed for this variant.	oncokb
BS4	Not met	No segregation data in affected families are available. Lack of segregation with disease cannot be demonstrated without pedigree information.
BP1	Not met	While loss-of-function variants in NTRK2 have been implicated in germline disease, there is insufficient evidence that NTRK2-associated disease is caused primarily by truncating variants to the exclusion of missense changes. BP1 cannot be applied.	pvs1_gene_context
BP2	Not met	Not observed in trans (or cis) with a pathogenic variant. No phasing or co-occurrence data are available.
BP4	Not met	REVEL score 0.77 predicts a deleterious effect, which contradicts benign computational predictions. Multiple lines of computational evidence do NOT uniformly suggest no impact on the gene product; BP4 is not supported.	revel bayesdel spliceai
BP5	Not met	No observation of this variant in a case with an alternate molecular basis for disease. No case-level data are available.
BP6	Not met	No reputable source reports this variant as benign. The variant is absent from ClinVar.	clinvar
BP7	N/A	BP7 is reserved for synonymous variants with no predicted splice impact. NM_006180.4:c.2061C>A is a missense variant (p.His687Gln), not a synonymous change.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions; NM_006180.4:c.2061C>A is a single-nucleotide substitution.
PM3	N/A	PM3 requires detection in trans with a pathogenic variant for recessive disorders; no second-variant data are available and inheritance pattern is not established.
PM4	N/A	PM4 applies to in-frame deletions/insertions or stop-loss variants that alter protein length; NM_006180.4:c.2061C>A is a single-nucleotide missense substitution.

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