Variant classification summary

NM_006180.4:c.1529C>A

NTRK2 · NP_006171.2:p.(Ser510Ter) · NM_006180.4

GRCh37: chr9:87482242 C>A · GRCh38: chr9:84867327 C>A

Gene: NTRK2 Transcript: NM_006180.4

Final call

Likely Pathogenic

PVS1 very strong PM2 moderate

Variant details

Gene

NTRK2

Transcript

NM_006180.4

Protein

NP_006171.2:p.(Ser510Ter)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, meeting PM2 at moderate strength.

3

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.

4

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.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

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	Met	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.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 applies to a nucleotide change predicting the same missense amino acid as an established pathogenic variant. This variant is a nonsense change (p.Ser510Ter), not a missense variant.
PS2	Not met	No de novo data are available for this variant. No parental testing or family studies were identified in the evidence record.
PS3	Not met	No well-established functional studies assessing the damaging effect of NM_006180.4:c.1529C>A were identified. No variant-specific functional data were found in the literature or curated databases.
PS4	Not met	No case-control or prevalence data are available. The variant is absent from ClinVar and no affected individuals have been reported in the literature.
PS5	N/A	PS5 is not a criterion in the standard ACMG/AMP 2015 framework (PMID:25741868). Even under extended frameworks that define PS5 as a novel missense at a residue with a different established pathogenic missense, this variant is a nonsense change and the criterion does not apply.
PM1	Not met	The variant does not lie in a statistically significant mutational hotspot. No critical functional domain has been specifically identified as enriched for pathogenic variation in NTRK2 through a CSPEC/VCEP framework. BayesDel score of 0.66 provides modest in silico support but does not independently establish a functional domain.	bayesdel
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	PM5 applies to a novel missense change at an amino acid residue where a different missense change has been established as pathogenic. This variant is a nonsense change (p.Ser510Ter), not a missense variant. The automated PM5 candidate search could not identify classic same-residue comparators and returned a not_applicable recommendation.	pm5_candidates
PM6	Not met	No de novo event has been reported for this variant. PM6 requires confirmation of de novo occurrence with both parental relationships confirmed; no such data are available.
PP1	Not met	No co-segregation data are available. No family studies or pedigree information for this variant were identified.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation where missense is a common disease mechanism. This variant is a nonsense change. Additionally, no HCI prior probability score is available for NTRK2 to support PP2 assessment even by extension.
PP3	N/A	PP3 applies to computational evidence supporting a deleterious effect for variants where the effect is not already established by a higher-tier criterion. This is a nonsense variant with an established loss-of-function mechanism already captured by PVS1. BayesDel score of 0.66 and SpliceAI max delta of 0.19 are noted but are not designed for nonsense variant assessment and do not independently support PP3.	bayesdel spliceai
PP4	Not met	No patient phenotype or family history information is available. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology; no clinical data were provided for this assessment.
PP5	Not met	No reputable source has classified this variant as pathogenic. The variant is absent from ClinVar; no submitters have reported a classification.	clinvar
BA1	Not met	The variant is absent from all population databases (gnomAD v2.1, v4.1, gnomAD-Canada). The allele frequency is 0%, well below the BA1 threshold of >1%.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from all population databases. The allele frequency is 0%, well below the BS1 threshold of >0.3% (or higher for recessive disorders).	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No data are available on observation of this variant in healthy adults. Population databases show zero observations, so no evidence of healthy adult carriers exists.
BS3	Not met	No well-established functional studies demonstrating no damaging effect of this variant were identified. No variant-specific functional data were found.
BS4	Not met	No segregation data are available to assess lack of co-segregation with disease. No family studies were identified.
BP1	N/A	BP1 applies to missense variants in genes where primarily truncating variants cause disease. This variant is a truncating (nonsense) variant, not a missense change. BP1 is not applicable.
BP2	Not met	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. No phase information is available.
BP4	N/A	BP4 applies to computational evidence suggesting no impact for variants where the effect is ambiguous. This is a nonsense variant with an established loss-of-function mechanism already captured by PVS1. SpliceAI max delta score of 0.19 predicts no cryptic splicing effect, but this does not independently support a benign interpretation given the clear LoF mechanism.	spliceai
BP5	Not met	No evidence exists that this variant has been found in a case with an alternate molecular basis for disease. No clinical data are available for the proband.
BP6	Not met	No reputable source has classified this variant as benign. The variant is absent from ClinVar; no submitters have reported a benign classification.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted impact on splicing. This variant is a nonsense change (p.Ser510Ter), not synonymous. BP7 is not applicable.

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