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NTRK2c.1529C>ALikely pathogenic
Print report
Variant interpretation report

NTRK2 c.1529C>A, p.(Ser510Ter)

NM_006180.4:c.1529C>A NP_006171.2:p.(Ser510Ter) View identifiers
Classification
Likely pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.

Likely pathogenic.A likely pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About NTRK2

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong

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.

PM2Moderate
PM2 · moderate

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.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

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.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.190 maximum delta

Recorded SpliceAI maximum delta score: 0.190. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

26 criteria with recorded statuses: 2 met · 16 not met · 0 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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.

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

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.

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.

Met · 2

PVS1 Very strongNM_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. Details ▾Hide ▴
Evidence considered
  • Nonsense variant (p.Ser510Ter) in exon 16/20 of NTRK2
  • NTRK2 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)
Still missing
  • Pipeline-derived PVS1 gene-context supporting literature (PMIDs 42018264
  • 30717682
  • 32082673
  • 39112663
  • 39341363) does not actually provide evidence for NTRK2 germline LoF disease mechanism
  • each paper addresses unrelated topics (APBA1/BSN obesity
  • somatic cancer panels
  • somatic NTRK2 fusions in glioma
  • TrkB pharmacology in Huntington's disease and Christianson syndrome). The gene-level conclusion that NTRK2 LoF is a disease mechanism is correct based on established OMIM curation
  • but the pipeline's literature support is spurious and should not be cited.
  • Confirm that NM_006180.4 is the biologically relevant transcript for the patient's indication.
Sources
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment
PM2 ModerateNM_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. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (0 alleles)
  • Absent from gnomAD v4.1 (0 alleles)
  • Absent from gnomAD-Canada v1.0 (0 alleles)
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 16 · evaluated, threshold not reached

PS2 No de novo data are available for this variant. No parental testing or family studies were identified in the evidence record. Details ▾Hide ▴
Still missing
  • No parental testing or trio data available
PS3 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. Details ▾Hide ▴
Still missing
  • No functional studies available for this variant
PS4 No case-control or prevalence data are available. The variant is absent from ClinVar and no affected individuals have been reported in the literature. Details ▾Hide ▴
Still missing
  • No affected individuals reported
  • no case-control data
PM1 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. Details ▾Hide ▴
Evidence considered
  • Not in a statistically significant hotspot per CancerHotspots.org
  • BayesDel score 0.66 (above 0.5 threshold but not independently sufficient for PM1)
Still missing
  • No CSPEC/VCEP-defined critical domain for NTRK2
Sources
bayesdel
PM6 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. Details ▾Hide ▴
Still missing
  • No de novo testing data available
PP1 No co-segregation data are available. No family studies or pedigree information for this variant were identified. Details ▾Hide ▴
Still missing
  • No family segregation data available
PP4 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. Details ▾Hide ▴
Still missing
  • No clinical phenotype data available for the proband
PP5 No reputable source has classified this variant as pathogenic. The variant is absent from ClinVar; no submitters have reported a classification. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar (no classifications available)
Sources
clinvar ↗
BA1 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%. Details ▾Hide ▴
Evidence considered
  • Allele frequency 0% in gnomAD v2.1
  • Allele frequency 0% in gnomAD v4.1
  • Allele frequency 0% in gnomAD-Canada
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 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). Details ▾Hide ▴
Evidence considered
  • Allele frequency 0% in gnomAD v2.1
  • Allele frequency 0% in gnomAD v4.1
  • Allele frequency 0% in gnomAD-Canada
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS2 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. Details ▾Hide ▴
Still missing
  • No data on healthy adult carriers
BS3 No well-established functional studies demonstrating no damaging effect of this variant were identified. No variant-specific functional data were found. Details ▾Hide ▴
Still missing
  • No functional studies available
BS4 No segregation data are available to assess lack of co-segregation with disease. No family studies were identified. Details ▾Hide ▴
Still missing
  • No family segregation data available
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. No phase information is available. Details ▾Hide ▴
Still missing
  • No phase or trans/cis data available
BP5 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. Details ▾Hide ▴
Still missing
  • No clinical or alternate-molecular-basis data available
BP6 No reputable source has classified this variant as benign. The variant is absent from ClinVar; no submitters have reported a benign classification. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar (no benign classifications available)
Sources
clinvar ↗
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 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. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 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. Details ▾Hide ▴
Sources
pm5_candidates
PP2 N/APP2 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. Details ▾Hide ▴

No further detail was recorded.

PP3 N/APP3 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. Details ▾Hide ▴
Evidence considered
  • BayesDel score 0.66 (moderate
  • but designed for missense assessment)
  • SpliceAI max delta 0.19 (no significant splice impact predicted)
Sources
bayesdelspliceai ↗
BP1 N/ABP1 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. Details ▾Hide ▴

No further detail was recorded.

BP4 N/ABP4 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. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.19 (no significant splice impact predicted)
Sources
spliceai ↗
BP7 N/ABP7 applies to synonymous variants with no predicted impact on splicing. This variant is a nonsense change (p.Ser510Ter), not synonymous. BP7 is not applicable. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 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. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
NTRK2
Transcript
NM_006180.4
Coding (HGVS c.)
NM_006180.4:c.1529C>A
Protein (HGVS p.)
NP_006171.2:p.(Ser510Ter)
GRCh38
chr9:84867327 C>A
GRCh37
chr9:87482242 C>A

Gene diagram

Every interpreted variant in NTRK2, mapped onto the exon structure of NM_006180.4. Select a row to find it on the plot.

NTRK2NM_006180.4
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +6 bp
0.080
SpliceAI acceptor gainat +2 bp
0.190
SpliceAI donor lossat -267 bp
0.000
SpliceAI donor gainat +2 bp
0.000
Pangolin splice lossmagnitude shown
-0.050
Pangolin splice gain
0.070

Other predictors

REVEL
Not available
BayesDel
0.660

How the predictions were used

PP3 N/APP3 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. Details ▾Hide ▴
Evidence considered
  • BayesDel score 0.66 (moderate
  • but designed for missense assessment)
  • SpliceAI max delta 0.19 (no significant splice impact predicted)
Sources
bayesdelspliceai ↗
BP4 N/ABP4 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. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.19 (no significant splice impact predicted)
Sources
spliceai ↗
BP7 N/ABP7 applies to synonymous variants with no predicted impact on splicing. This variant is a nonsense change (p.Ser510Ter), not synonymous. BP7 is not applicable. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.19). BayesDel score = 0.66.

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.190 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.19). BayesDel score = 0.66.

Functional

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.