NM_006180.4:c.2033C>T (p.Ala678Val) in NTRK2 is a missense variant for which no CSPEC or VCEP gene-specific framework is available; classification proceeds under generic ACMG/AMP 2015 guidelines.1 This variant is absent from gnomAD v2.1 and gnomAD-Canada, and is present at an extremely low frequency in gnomAD v4.1 (4/1,613,948 alleles, AF = 2.48e-06, 0.00025%), meeting PM2 at supporting strength.2 No pathogenic or benign criteria beyond PM2_supporting were met. PVS1/BP7 are not applicable to this missense variant. In silico predictors are discordant (REVEL 0.654 damaging, BayesDel 0.073 benign, SpliceAI delta 0.00), so PP3 and BP4 are not met. No functional studies, segregation data, de novo reports, or hotspot evidence were available.3 The variant is reported in ClinVar (Variation ID 1393489) as Uncertain significance by a single clinical laboratory (Labcorp Genetics, SCV002166224), consistent with the limited evidence available for classification.4 With only one supporting pathogenic criterion (PM2) met and no benign criteria met, this variant is classified as a Variant of Uncertain Significance (VUS) under the generic ACMG/AMP 2015 framework.5
NTRK2
Final classification
VUS
PM2
NTRK2
c.2033C>T
p.Ala678Val
This variant
NM_006180.4:c.2033C>T (p.Ala678Val) in NTRK2 is a missense variant for which no CSPEC or VCEP gene-specific framework is available; classification proceeds under generic ACMG/AMP 2015 guidelines.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting; combination = 1 supporting, which maps to VUS.
Classification rationale
PM2
VUS
NTRK2 c.2033C>T
PM2
→
VUS
Gene diagram
· NM_006180.4 · variants mapped to exon structure
NTRK2
NM_006180.4
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 20 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
NM_006180.4:c.2033C>T is absent from gnomAD v2.1 and gnomAD-Canada, and is present at an extremely low allele frequency in gnomAD v4.1 (AF = 2.48e-06, 4/1,613,948 alleles, 0.00025%), well below the 0.1% threshold for PM2. This supports a pathogenic role under population-level rarity.
gnomAD v2.1: absent.gnomAD v4.1: 4/1613
Assessed · not applied
· 19 not met · 1 not assessed
Pathogenic
PS1
No alternative nucleotide change at the same amino acid residue (Ala678) has been reported as pathogenic in ClinVar or the literature.
PS2
No de novo observation of NM_006180.4:c.2033C>T has been reported in the available evidence.
PS3
No well-established functional studies demonstrate a damaging effect of p.Ala678Val on NTRK2 protein function.
PS4
The prevalence of NM_006180.4:c.2033C>T in affected individuals has not been shown to be significantly increased compared to controls.
PM1
Although p.Ala678Val resides within the tyrosine kinase domain of NTRK2 (amino acids ~544–821), cancer hotspot analysis did not identify this residue or surrounding region as a statistically significant mutational hotspot, and no functional domain-level constraint data are available to satisfy PM1.
PM6
No confirmed de novo observation of NM_006180.4:c.2033C>T has been reported with maternity and paternity confirmed.
PP1
No co-segregation data are available for NM_006180.4:c.2033C>T in affected families.
PP2
PP2 requires a gene with a low rate of benign missense variation where missense variants are a common disease mechanism.
PP3
In silico predictions are discordant: REVEL (0.654) predicts a damaging effect while BayesDel (0.073) predicts a benign effect, and SpliceAI (max delta = 0.00) shows no splice-altering potential.
PP4
No evidence that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology attributable to NTRK2.
PP5
No reputable source has independently classified this variant as pathogenic.
Benign
BA1
The variant allele frequency in gnomAD v4.1 (AF = 2.48e-6, 0.00025%) is well below the BA1 threshold of 1% (AF > 0.01).
BS1
The variant allele frequency in gnomAD v4.1 (AF = 2.48e-6, 0.00025%) is well below the BS1 threshold of 0.3% (AF > 0.003).
BS2
No evidence that this variant has been observed in a healthy adult individual, either in trans with a known pathogenic variant in a recessive disorder, or in homozygous state in a healthy adult for a fully penetrant dominant disorder.
BS3
No well-established functional studies demonstrate no deleterious effect of p.Ala678Val on NTRK2 protein function or splicing.
BS4
No segregation data are available to demonstrate lack of co-segregation with disease in affected families.
BP2
No evidence that this variant has been observed in trans with a known pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant in any inheritance pattern.
BP4
Computational evidence is discordant: REVEL (0.654) predicts a damaging effect, while BayesDel (0.073) predicts a benign effect.
BP5
No evidence contradicting pathogenicity is available.
BP6
No reputable source has classified this variant as benign or likely benign.
N/A · 4
PVS1 · PM5 · BP1 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 2.47839e-06; MAF= 0.00025%, 4/1613948 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 3.37815e-05; MAF= 0.00338%, 1/29602 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
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
0.00025%
· 4 / 1,613,948
0 hom · FAF 2.8e-05%
0 hom · FAF 2.8e-05%
Ashkenazi Jewish 1 / 29,602 |
0.0034% |
East Asian 1 / 44,888 |
0.0022% |
European (non-Finnish) 2 / 1,179,956 |
0.00017% |
+ 7 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, African/African American)
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 1393489)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.654. BayesDel score = 0.072725.
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52875759, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links