NM_006180.4:c.1529C>A is a nonsense variant in NTRK2 predicting p.(Ser510Ter), meeting PVS1 at very strong strength under the ClinGen SVI PVS1 framework (PMC6185798). NTRK2 loss-of-function is an established mechanism for autosomal dominant obesity, hyperphagia, and developmental delay (MIM #613886). The premature termination codon in exon 16 of 20 is predicted to trigger nonsense-mediated decay.1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, meeting PM2 at moderate strength.2 Applying generic ACMG/AMP 2015 combination rules (PMID:25741868): one Very Strong criterion (PVS1) plus one Moderate criterion (PM2) meets the threshold for Pathogenic classification.3 The pipeline-derived PVS1 gene-context literature search returned five supporting papers (PMIDs 42018264, 30717682, 32082673, 39112663, 39341363), but none of these papers mention NM_006180.4:c.1529C>A or provide evidence for NTRK2 germline loss-of-function as a disease mechanism. The gene-level PVS1 eligibility determination is independently supported by established OMIM curation (MIM #613886) rather than by the pipeline's literature search results.
NTRK2
Final classification
Likely Pathogenic
PVS1PM2
NTRK2
c.1529C>A
p.Ser510Ter
This variant
NM_006180.4:c.1529C>A is a nonsense variant in NTRK2 predicting p.(Ser510Ter), meeting PVS1 at very strong strength under the ClinGen SVI PVS1 framework (PMC6185798). NTRK2 loss-of-function is an established mechanism for autosomal dominant obesity, hyperphagia, and developmental delay (MIM #613886). The premature termination codon in exon 16 of 20 is predicted to trigger nonsense-mediated decay.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 moderate; combination = 1 very strong + 1 moderate, which maps to Likely Pathogenic.
Classification rationale
PVS1PM2
Likely Pathogenic
NTRK2 c.1529C>A
PVS1 + PM2
→
Likely Pathogenic
1
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment
3
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 · 16 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 · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
very strong
review
Pathogenic
NM_006180.4:c.1529C>A is a nonsense variant predicting p.(Ser510Ter) in exon 16 of 20 coding exons of NTRK2. NTRK2 is a recognized germline disease gene where loss-of-function is an established mechanism for autosomal dominant obesity, hyperphagia, and developmental delay (MIM #613886). The premature termination codon at position 510 lies 644 nucleotides upstream of the final exon-exon junction, predicting nonsense-mediated decay. Under the ClinGen SVI PVS1 framework (PMC6185798), this meets PVS1 at very strong strength.
Nonsense variant (p.Ser510Ter) in exon 16/20 of NTRK2NTRK2 loss-of-function is an established germline disease mechanism for obesity/hyperphagia/developmental delay (MIM #613886)Premature termination codon at codon 510 is predicted to trigger nonsense-mediated decay (644 nucleotides upstream of final exon-exon junction)
✓
PM2
moderate
Pathogenic
NM_006180.4:c.1529C>A is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (genomes/exomes), and gnomAD-Canada v1.0 (HostSeq genomes). Absence from large population databases in a gene where pathogenic variants are established meets PM2 at moderate strength under generic ACMG/AMP.
Absent from gnomAD v2.1 (0 alleles)Absent from gnomAD v4.1 (0 alleles)Absent from gnomAD-Canada v1.0 (0 alleles)
Assessed · not applied
· 16 not met · 0 not assessed
Pathogenic
PS2
No de novo data are available for this variant.
PS3
No well-established functional studies assessing the damaging effect of NM_006180.4:c.1529C>A were identified.
PS4
No case-control or prevalence data are available.
PM1
The variant does not lie in a statistically significant mutational hotspot.
PM6
No de novo event has been reported for this variant.
PP1
No co-segregation data are available.
PP4
No patient phenotype or family history information is available.
PP5
No reputable source has classified this variant as pathogenic.
Benign
BA1
The variant is absent from all population databases (gnomAD v2.1, v4.1, gnomAD-Canada).
BS1
The variant is absent from all population databases.
BS2
No data are available on observation of this variant in healthy adults.
BS3
No well-established functional studies demonstrating no damaging effect of this variant were identified.
BS4
No segregation data are available to assess lack of co-segregation with disease.
BP2
No data are available regarding observation of this variant in trans with a known pathogenic variant in NTRK2 or in cis with a pathogenic variant.
BP5
No evidence exists that this variant has been found in a case with an alternate molecular basis for disease.
BP6
No reputable source has classified this variant as benign.
N/A · 7
PS1 · PM5 · PP2 · PP3 · BP1 · BP4 · BP7
Research & evidence
Population frequency · supports pathogenic
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
0 hom
Not observed in any ancestry group.
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.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.19). BayesDel score = 0.66.
Functional
Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
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.
Sources & reference links