rs1432834509

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006180.6(NTRK2):​c.29C>A​(p.Pro10His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 33)

Consequence

NTRK2
NM_006180.6 missense

Scores

1
10
8

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.17
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NTRK2NM_006180.6 linkc.29C>A p.Pro10His missense_variant Exon 2 of 19 ENST00000277120.8 NP_006171.2 Q16620-4A0A024R230Q5VWE5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NTRK2ENST00000277120.8 linkc.29C>A p.Pro10His missense_variant Exon 2 of 19 1 NM_006180.6 ENSP00000277120.3 Q16620-4

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
Mar 19, 2024
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Nov 05, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 10 of the NTRK2 protein (p.Pro10His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NTRK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 2829547). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Uncertain
0.0
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.40
.;T;.;.;.;.;T;.
Eigen
Uncertain
0.38
Eigen_PC
Uncertain
0.39
FATHMM_MKL
Uncertain
0.83
D
LIST_S2
Benign
0.84
T;T;T;T;T;.;.;.
M_CAP
Uncertain
0.18
D
MetaRNN
Uncertain
0.72
D;D;D;D;D;D;D;D
MetaSVM
Uncertain
-0.22
T
MutationAssessor
Benign
1.0
L;L;L;L;L;L;L;L
PrimateAI
Uncertain
0.50
T
PROVEAN
Benign
-1.9
N;N;N;N;N;N;N;N
REVEL
Uncertain
0.42
Sift
Benign
0.069
T;T;D;D;D;T;T;D
Sift4G
Benign
0.51
T;T;T;D;D;T;T;T
Polyphen
1.0
D;D;D;D;D;D;D;D
Vest4
0.59
MutPred
0.47
Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);
MVP
0.86
MPC
1.9
ClinPred
0.86
D
GERP RS
4.1
Varity_R
0.21
gMVP
0.59

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1432834509; hg19: chr9-87285692; COSMIC: COSV52884748; API