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NTRK2c.2061C>AUncertain significance
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Variant interpretation report

NTRK2 c.2061C>A, p.(His687Gln)

NM_006180.4:c.2061C>A NP_006171.2:p.(His687Gln) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

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

Uncertain.The recorded classification is uncertain significance.

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: 1 Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Moderate
PM2 · moderate

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.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

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 moderate; combination = 1 moderate, which maps to VUS.

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
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. 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 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.

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.

29 criteria with recorded statuses: 1 met · 21 not met · 0 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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).

Met · 1

PM2 ModerateNM_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. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (exomes).
  • Absent from gnomAD v4.1 (exomes/genomes).
  • Absent from gnomAD-Canada v1.0 (HostSeq genomes).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 21 · evaluated, threshold not reached

PS1 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. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar
  • no pathogenic comparator with the same amino acid change identified.
Still missing
  • No ClinVar or literature data for any variant at p.His687.
Sources
clinvar ↗
PS2 No de novo observations (with maternity and paternity confirmed) have been reported for this variant. No family-based studies or trio data are available. Details ▾Hide ▴
Evidence considered
  • No de novo reports identified in any data source.
Still missing
  • No trio or family studies available.
PS3 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. Details ▾Hide ▴
Evidence considered
  • OncoKB reports unknown oncogenic effect with no variant-specific reviewed functional evidence.
  • No functional studies identified in literature.
Still missing
  • No in vitro or in vivo functional data for this variant.
Sources
oncokb ↗
PS4 No case-control studies or proband enrichment data are available. The variant has not been reported in affected individuals. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar and all population databases
  • no affected individuals reported.
Still missing
  • No case reports or cohort studies available.
Sources
clinvar ↗gnomad_v2 ↗gnomad_v4 ↗
PM1 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. Details ▾Hide ▴
Evidence considered
  • Residue not in a statistically significant hotspot.
  • No VCEP/CSPEC domain-level PM1 rule available for NTRK2.
Still missing
  • No domain-specific benign variation frequency data for NTRK2 kinase domain.
PM5 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. Details ▾Hide ▴
Evidence considered
  • No same-residue pathogenic comparators identified in ClinVar
  • zero PM5 candidates.
Still missing
  • No ClinVar entries for any variant at p.His687.
Sources
pm5_candidatesclinvar ↗
PM6 No assumed de novo observations (without maternity/paternity confirmation) have been reported for this variant. Details ▾Hide ▴
Evidence considered
  • No de novo reports identified in any data source.
Still missing
  • No trio or family data available.
PP1 No cosegregation data in affected families are available for this variant. Details ▾Hide ▴
Evidence considered
  • No family-based cosegregation studies identified.
Still missing
  • No family or pedigree data.
PP2 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. Details ▾Hide ▴
Evidence considered
  • HCI prior data unavailable for NTRK2.
  • No established low benign missense variation rate for this gene.
Still missing
  • No missense constraint metrics (Z-score
  • pLI for missense
  • missense OE ratio) available.
PP3 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. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.77 (deleterious).
  • BayesDel: 0.307 (borderline
  • does not strongly support pathogenicity).
  • SpliceAI: max delta 0.00 (no predicted splicing impact
  • neutral).
Still missing
  • Only one in silico predictor (REVEL) strongly supports deleterious effect
  • no concordant second predictor.
Sources
revelbayesdelspliceai ↗
PP4 No patient phenotype data are available. Assessment of phenotypic specificity for a single genetic etiology cannot be performed. Details ▾Hide ▴
Evidence considered
  • No clinical phenotype or family history data provided.
Still missing
  • No proband phenotype information.
BA1 Allele frequency does not exceed 1% in any population database. The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Details ▾Hide ▴
Evidence considered
  • Variant absent from all population databases
  • AF = 0.0%.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 Allele frequency does not exceed 0.3% in any population database. The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Details ▾Hide ▴
Evidence considered
  • Variant absent from all population databases
  • AF = 0.0%.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS2 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. Details ▾Hide ▴
Evidence considered
  • Variant absent from all population databases
  • no healthy adult carriers identified.
Still missing
  • No data on variant occurrence in healthy individuals.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 No well-established functional studies demonstrating no deleterious effect are available. No functional assays have been performed for this variant. Details ▾Hide ▴
Evidence considered
  • No functional studies identified
  • OncoKB reports unknown oncogenic effect.
Still missing
  • No in vitro or in vivo functional data for this variant.
Sources
oncokb ↗
BS4 No segregation data in affected families are available. Lack of segregation with disease cannot be demonstrated without pedigree information. Details ▾Hide ▴
Evidence considered
  • No family or cosegregation data available.
Still missing
  • No pedigree or family studies.
BP1 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. Details ▾Hide ▴
Evidence considered
  • LoF mechanism supported for NTRK2
  • but insufficient evidence that disease is exclusively truncating-mediated.
  • No ClinGen guidance on NTRK2 disease mechanism.
Still missing
  • No curated gene-disease validity assessment for NTRK2 missense vs truncating mechanism.
Sources
pvs1_gene_context
BP2 Not observed in trans (or cis) with a pathogenic variant. No phasing or co-occurrence data are available. Details ▾Hide ▴
Evidence considered
  • No co-occurrence or phasing data available.
Still missing
  • No data on variant phase with other pathogenic variants.
BP4 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. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.77 (deleterious).
  • BayesDel: 0.307 (borderline).
  • SpliceAI: max delta 0.00 (no splicing impact).
Sources
revelbayesdelspliceai ↗
BP5 No observation of this variant in a case with an alternate molecular basis for disease. No case-level data are available. Details ▾Hide ▴
Evidence considered
  • No case data available to evaluate alternate molecular etiology.
Still missing
  • No proband-level molecular workup data.
BP6 No reputable source reports this variant as benign. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no benign classification from any source.
Sources
clinvar ↗
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 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). Details ▾Hide ▴
Evidence considered
  • Variant is a missense substitution
  • not a null variant
  • excluded from PVS1 per PVS1 decision tree.
Sources
pvs1_generic_framework ↗
PM3 N/APM3 requires detection in trans with a pathogenic variant for recessive disorders; no second-variant data are available and inheritance pattern is not established. Details ▾Hide ▴
Evidence considered
  • No second variant data
  • inheritance pattern not established.
PM4 N/APM4 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. Details ▾Hide ▴
Evidence considered
  • Variant is a missense substitution
  • not a protein-length-altering variant.
PP5 N/APP5 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. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • PP5 not a standard ACMG/AMP criterion.
Sources
clinvar ↗
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions; NM_006180.4:c.2061C>A is a single-nucleotide substitution. Details ▾Hide ▴
Evidence considered
  • Variant is a substitution
  • not an in-frame indel.
BP7 N/ABP7 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. Details ▾Hide ▴
Evidence considered
  • Variant is missense (p.His687Gln)
  • not synonymous.
PS5 N/APS5 is not part of the standard ACMG/AMP 2015 criteria (PMID:25741868). No equivalent evidence tier applies. Details ▾Hide ▴
Evidence considered
  • PS5 is not a standard ACMG/AMP criterion.

Identifiers

Gene
NTRK2
Transcript
NM_006180.4
Coding (HGVS c.)
NM_006180.4:c.2061C>A
Protein (HGVS p.)
NP_006171.2:p.(His687Gln)
GRCh38
chr9:84955406 C>A
GRCh37
chr9:87570321 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 -148 bp
0.000
SpliceAI acceptor gainat +27 bp
0.000
SpliceAI donor lossat -295 bp
0.000
SpliceAI donor gainat -224 bp
0.000
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.010

Other predictors

REVEL
0.770
BayesDel
0.307

How the predictions were used

PP3 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. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.77 (deleterious).
  • BayesDel: 0.307 (borderline
  • does not strongly support pathogenicity).
  • SpliceAI: max delta 0.00 (no predicted splicing impact
  • neutral).
Still missing
  • Only one in silico predictor (REVEL) strongly supports deleterious effect
  • no concordant second predictor.
Sources
revelbayesdelspliceai ↗
BP4 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. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.77 (deleterious).
  • BayesDel: 0.307 (borderline).
  • SpliceAI: max delta 0.00 (no splicing impact).
Sources
revelbayesdelspliceai ↗
BP7 N/ABP7 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. Details ▾Hide ▴
Evidence considered
  • Variant is missense (p.His687Gln)
  • not synonymous.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.77. BayesDel score = 0.307499.

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 0.000 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 = 0.00). REVEL score = 0.77. BayesDel score = 0.307499.

Functional

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.

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.