rs886041091

Positions:

• chr9-84751990-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP2 PP3 PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• 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]

ACMG classification

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

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	26
DANN	Uncertain	0.99
Eigen	Pathogenic	0.68
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;.;.;.
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Uncertain	2.2	M;M;M;M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-4.3	D;D;D;D;D;D;D;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.010	D;D;D;D;D;D;D;D
Sift4G	Benign	0.092	T;T;D;D;D;T;T;D
Polyphen		0.58	P;B;D;P;D;P;B;D
Vest4		0.83
MutPred		0.50		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		0.88
MPC		1.9
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.32
gMVP		0.85

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

Other links and lift over

dbSNP: rs886041091; hg19: chr9-87366905;