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NTRK2c.1937G>AUncertain significance
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Variant interpretation report

NTRK2 c.1937G>A, p.(Arg646Lys)

NM_006180.4:c.1937G>A NP_006171.2:p.(Arg646Lys) 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: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting

NM_006180.4:c.1937G>A is absent from all large population cohorts, including gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. This satisfies PM2 at supporting level under generic ACMG/AMP (allele frequency <0.1%).

PP3Supporting
PP3 · supporting

Multiple in silico predictors support a deleterious effect for NM_006180.4:c.1937G>A. REVEL score is 0.776 (pathogenic range, >0.5). SpliceAI predicts a cryptic donor gain (max delta score = 0.53, DS_DG = 0.53) suggesting potential splice alteration. BayesDel score is 0.27 (borderline damaging). The convergent prediction from independent tools supports PP3 at supporting level.

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 supporting, PP3 supporting; combination = 2 supporting, 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
0.530 maximum delta

Recorded SpliceAI maximum delta score: 0.530. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 → 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.

26 criteria with recorded statuses: 2 met · 22 not met · 0 not assessed · 2 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.1937G>A (p.Arg646Lys) is a missense variant in the NTRK2 kinase domain (exon 18). It is absent from all large population cohorts (gnomAD v2.1, v4.1, gnomAD-Canada), meeting PM2 at supporting level.

Multiple in silico tools predict a deleterious effect: REVEL score 0.776 (pathogenic range), SpliceAI max delta 0.53 with a predicted donor gain, and BayesDel 0.27, meeting PP3 at supporting level.

No variant-specific functional studies, de novo observations, segregation data, or ClinVar classifications exist for this variant. The variant has not been reported in the literature.

Under generic ACMG/AMP 2015 combination rules: PM2_Supporting + PP3_Supporting = one supporting pathogenic criterion. This does not reach the threshold for Likely Pathogenic (requires ≥2 supporting or ≥1 moderate). The variant is classified as a Variant of Uncertain Significance (VUS).

Met · 2

PM2 SupportingNM_006180.4:c.1937G>A is absent from all large population cohorts, including gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. This satisfies PM2 at supporting level under generic ACMG/AMP (allele frequency <0.1%). 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 ↗
PP3 SupportingMultiple in silico predictors support a deleterious effect for NM_006180.4:c.1937G>A. REVEL score is 0.776 (pathogenic range, >0.5). SpliceAI predicts a cryptic donor gain (max delta score = 0.53, DS_DG = 0.53) suggesting potential splice alteration. BayesDel score is 0.27 (borderline damaging). The convergent prediction from independent tools supports PP3 at supporting level. Details ▾Hide ▴
Evidence considered
  • REVEL score 0.776 (predicted pathogenic).
  • SpliceAI max delta score 0.53
  • donor gain prediction (DS_DG = 0.53
  • DP_DG = 5 bp).
  • BayesDel score 0.27 (borderline damaging).
Sources
revelspliceai ↗bayesdel

Not met · 22 · evaluated, threshold not reached

PS1 No established pathogenic variant with the same amino acid change (p.Arg646Lys) arising from a different nucleotide substitution was identified in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
  • ClinVar contains no entries for NM_006180.4:c.1937G>A or any other variant resulting in p.Arg646Lys.
Still missing
  • No same-residue pathogenic comparators available for PS1 assessment.
Sources
clinvar ↗
PS2 No de novo observation has been reported for NM_006180.4:c.1937G>A in the literature or public databases. Details ▾Hide ▴
Evidence considered
  • No de novo data available from any source.
Still missing
  • No family studies or de novo reports identified.
PS3 No variant-specific functional studies have been published for NM_006180.4:c.1937G>A (p.Arg646Lys). OncoKB classifies this variant as 'Unknown Oncogenic Effect' with no reviewed functional evidence. No systematic functional characterization of the surrounding region exists in the literature. Details ▾Hide ▴
Evidence considered
  • OncoKB reports no variant-specific functional evidence
  • no experimental studies identified in literature search.
Still missing
  • No functional data exists for this variant or any systematically characterized range that includes it.
Sources
oncokb ↗
PS4 No case-control studies or statistical enrichment data exist for NM_006180.4:c.1937G>A in affected individuals versus controls. Details ▾Hide ▴
Evidence considered
  • No published case-control or cohort studies identified.
Still missing
  • No affected-individual enrichment data available.
PM1 Although p.Arg646Lys resides within the NTRK2 kinase domain, no residue-specific mutational hotspot has been identified at this position (cancerhotspots.org negative), and no variant-specific functional or clinical evidence establishes this as a critical functional domain residue for germline disease. Details ▾Hide ▴
Evidence considered
  • Cancerhotspots.org does not identify this residue as a statistically significant hotspot
  • no domain-level constraint or mutational enrichment data available for this position.
Still missing
  • No residue-specific hotspot or domain-level pathogenic enrichment data available for this position in NTRK2.
Sources
oncokb ↗
PM5 No pathogenic missense variant at the same amino acid residue (Arg646) has been reported in ClinVar or the literature. The PM5 candidate search returned zero same-residue comparator variants. Details ▾Hide ▴
Evidence considered
  • Zero same-residue pathogenic comparator variants identified in ClinVar.
Still missing
  • No same-residue pathogenic missense variants available for PM5 comparison.
Sources
pm5_candidatesclinvar ↗
PM6 No de novo observation (with or without confirmed maternity/paternity) has been reported for NM_006180.4:c.1937G>A. Details ▾Hide ▴
Evidence considered
  • No de novo reports in literature or databases.
Still missing
  • No de novo studies available for this variant.
PP1 No co-segregation data are available for NM_006180.4:c.1937G>A; no family studies have been reported. Details ▾Hide ▴
Evidence considered
  • No co-segregation or family studies identified.
Still missing
  • No family-based segregation data available.
PP2 PP2 requires a gene with a low rate of benign missense variation (high missense constraint z-score) where missense variants are an established mechanism of disease. No gnomAD missense constraint data were available for NTRK2 in the evidence packet, precluding application of PP2. Details ▾Hide ▴
Evidence considered
  • No missense constraint metrics (z-score
  • o/e
  • pLI) available in case data for NTRK2.
Still missing
  • Missing gnomAD gene constraint metrics needed to evaluate PP2.
PP4 No patient phenotype or family history data are available for this case. PP4 requires a phenotype highly specific for the gene/disease, which cannot be assessed without clinical context. Details ▾Hide ▴
Evidence considered
  • No patient phenotype data provided.
Still missing
  • Patient phenotype and clinical history not available for PP4 assessment.
PP5 No reputable source has reported NM_006180.4:c.1937G>A as pathogenic. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no external classification as pathogenic.
Sources
clinvar ↗
BA1 NM_006180.4:c.1937G>A is absent from all population databases (gnomAD v2.1, v4.1, gnomAD-Canada). BA1 requires an allele frequency >5%. Details ▾Hide ▴
Evidence considered
  • Variant allele frequency is 0% across all gnomAD populations
  • far below the BA1 >5% threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 NM_006180.4:c.1937G>A is absent from population databases. BS1 requires an allele frequency greater than expected for the disorder (>0.3% under generic ACMG). Details ▾Hide ▴
Evidence considered
  • Variant allele frequency is 0% across all gnomAD populations
  • below the BS1 >0.3% threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 No observation of NM_006180.4:c.1937G>A in a healthy adult has been reported for a fully penetrant disorder. The variant is absent from population databases. Details ▾Hide ▴
Evidence considered
  • No observations in healthy adult controls or population databases.
Still missing
  • No healthy-adult observation data available.
BS3 No functional studies demonstrating a benign effect for NM_006180.4:c.1937G>A have been published. OncoKB reports no variant-specific functional evidence. Details ▾Hide ▴
Evidence considered
  • No in vitro or in vivo functional studies showing no damaging effect identified.
Still missing
  • No functional data available to support a benign effect.
Sources
oncokb ↗
BS4 No segregation data are available for NM_006180.4:c.1937G>A. BS4 requires lack of segregation in affected family members, which cannot be assessed without family-based genotype data. Details ▾Hide ▴
Evidence considered
  • No family segregation data available.
Still missing
  • No co-segregation studies to evaluate BS4.
BP1 BP1 applies when a missense variant occurs in a gene where only truncating variants cause disease. While NTRK2 loss-of-function is supported as a disease mechanism, missense variants have also been implicated in germline disease (e.g., kinase-domain missense variants reported in developmental disorders), so a truncating-only mechanism cannot be assumed. Details ▾Hide ▴
Evidence considered
  • NTRK2 disease mechanism includes both truncating and missense variants
  • BP1 criteria not satisfied.
Sources
pvs1_gene_context
BP2 No observation of NM_006180.4:c.1937G>A in trans with a known pathogenic variant has been reported for a fully penetrant disorder. Details ▾Hide ▴
Evidence considered
  • No trans-configuration observations available.
Still missing
  • No phase data or observations in trans.
BP4 Multiple in silico predictors suggest a deleterious effect rather than a benign effect. REVEL score is 0.776 (pathogenic range) and SpliceAI predicts splice alteration (max delta = 0.53). BP4 requires multiple lines of computational evidence suggesting no impact, which is contradicted by the observed scores. Details ▾Hide ▴
Evidence considered
  • REVEL 0.776 is in the predicted pathogenic range
  • contradicting BP4.
  • SpliceAI 0.53 predicts potential splice alteration
Sources
revelspliceai ↗bayesdel
BP5 No case has been reported in which NM_006180.4:c.1937G>A was found in an individual with an alternate molecular basis for disease. Details ▾Hide ▴
Evidence considered
  • No alternate-molecular-basis observations available.
Still missing
  • No case-level data for alternate molecular etiology.
BP6 No reputable source has reported NM_006180.4:c.1937G>A as benign. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no external classification as benign.
Sources
clinvar ↗
PS5 No reputable source (e.g., clinical diagnostic laboratory) has reported NM_006180.4:c.1937G>A as pathogenic in the absence of accessible evidence. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no external classification as pathogenic from any source.
Sources
clinvar ↗
Not applicable · 2· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is reserved for null variants (nonsense, frameshift, canonical ±1,2 splice sites). NM_006180.4:c.1937G>A is a missense variant (p.Arg646Lys) and does not fall into any PVS1 null-variant bucket per ClinGen SVI recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
  • Missense variant does not qualify for null-variant PVS1 criteria
  • variant bucket classified as 'other' per PVS1 variant assessment.
Sources
pvs1_generic_framework ↗
BP7 N/ABP7 applies to synonymous variants predicted to have no splice impact. NM_006180.4:c.1937G>A is a missense variant (p.Arg646Lys), not a synonymous variant. Details ▾Hide ▴
Evidence considered
  • Variant is missense
  • not synonymous
  • BP7 is not applicable.

Identifiers

Gene
NTRK2
Transcript
NM_006180.4
Coding (HGVS c.)
NM_006180.4:c.1937G>A
Protein (HGVS p.)
NP_006171.2:p.(Arg646Lys)
GRCh38
chr9:84948634 G>A
GRCh37
chr9:87563549 G>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 +336 bp
0.000
SpliceAI acceptor gainat +130 bp
0.000
SpliceAI donor lossat +0 bp
0.070
SpliceAI donor gainat +5 bp
0.530
Pangolin splice lossmagnitude shown
-0.450
Pangolin splice gain
0.200

Other predictors

REVEL
0.776
BayesDel
0.270

How the predictions were used

PP3 SupportingMultiple in silico predictors support a deleterious effect for NM_006180.4:c.1937G>A. REVEL score is 0.776 (pathogenic range, >0.5). SpliceAI predicts a cryptic donor gain (max delta score = 0.53, DS_DG = 0.53) suggesting potential splice alteration. BayesDel score is 0.27 (borderline damaging). The convergent prediction from independent tools supports PP3 at supporting level. Details ▾Hide ▴
Evidence considered
  • REVEL score 0.776 (predicted pathogenic).
  • SpliceAI max delta score 0.53
  • donor gain prediction (DS_DG = 0.53
  • DP_DG = 5 bp).
  • BayesDel score 0.27 (borderline damaging).
Sources
revelspliceai ↗bayesdel
BP4 Multiple in silico predictors suggest a deleterious effect rather than a benign effect. REVEL score is 0.776 (pathogenic range) and SpliceAI predicts splice alteration (max delta = 0.53). BP4 requires multiple lines of computational evidence suggesting no impact, which is contradicted by the observed scores. Details ▾Hide ▴
Evidence considered
  • REVEL 0.776 is in the predicted pathogenic range
  • contradicting BP4.
  • SpliceAI 0.53 predicts potential splice alteration
Sources
revelspliceai ↗bayesdel
BP7 N/ABP7 applies to synonymous variants predicted to have no splice impact. NM_006180.4:c.1937G>A is a missense variant (p.Arg646Lys), not a synonymous variant. Details ▾Hide ▴
Evidence considered
  • Variant is missense
  • not synonymous
  • BP7 is not applicable.

Statement

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.53). REVEL score = 0.776. BayesDel score = 0.269805.

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 0.530 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 possible splice impact for this variant (max delta score = 0.53). REVEL score = 0.776. BayesDel score = 0.269805.

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.