rs886041091
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP2PP3PP5_Very_Strong
The NM_006180.6(NTRK2):c.1301A>G(p.Tyr434Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
NTRK2
NM_006180.6 missense
NM_006180.6 missense
Scores
5
10
3
Clinical Significance
Conservation
PhyloP100: 5.72
Genes affected
NTRK2 (HGNC:8032): (neurotrophic receptor tyrosine kinase 2) This gene encodes a member of the neurotrophic tyrosine receptor kinase (NTRK) family. This kinase is a membrane-bound receptor that, upon neurotrophin binding, phosphorylates itself and members of the MAPK pathway. Signalling through this kinase leads to cell differentiation. Mutations in this gene have been associated with obesity and mood disorders. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, NTRK2
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.816
PP5
?
Variant 9-84751990-A-G is Pathogenic according to our data. Variant chr9-84751990-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 268204.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NTRK2 | NM_006180.6 | c.1301A>G | p.Tyr434Cys | missense_variant | 12/19 | ENST00000277120.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NTRK2 | ENST00000277120.8 | c.1301A>G | p.Tyr434Cys | missense_variant | 12/19 | 1 | NM_006180.6 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes | Jan 15, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 17, 2023 | This missense change has been observed in individual(s) with NTRK2-related conditions (PMID: 29100083). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 268204). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NTRK2 protein function. For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 434 of the NTRK2 protein (p.Tyr434Cys). - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 19, 2022 | Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34889524, 29100083, 29652076, 31070779, 34426522, 33816068) - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Jun 17, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2020 | - - |
Developmental and epileptic encephalopathy, 58 Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 09, 2020 | - - |
Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Nov 02, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Undiagnosed Diseases Network, NIH | Aug 21, 2018 | - - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 02, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;.;.;.
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M;M;M;M;M;M;M
MutationTaster
Benign
D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D;D;D;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;D;D;D;D;D;D
Sift4G
Benign
T;T;D;D;D;T;T;D
Polyphen
P;B;D;P;D;P;B;D
Vest4
MutPred
Loss of phosphorylation at Y434 (P = 0.1075);Loss of phosphorylation at Y434 (P = 0.1075);Loss of phosphorylation at Y434 (P = 0.1075);Loss of phosphorylation at Y434 (P = 0.1075);Loss of phosphorylation at Y434 (P = 0.1075);Loss of phosphorylation at Y434 (P = 0.1075);Loss of phosphorylation at Y434 (P = 0.1075);Loss of phosphorylation at Y434 (P = 0.1075);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at