rs121434633

Positions:

• chr9-84955510-A-G
• chr9-84955510-A-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PM5 PP2 PP3_Strong PP5

The NM_006180.6(NTRK2):​c.2165A>G​(p.Tyr722Cys) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y722D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NTRK2 NM_006180.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.32

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 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-84955509-T-G is described in Lovd as [Pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NTRK2. . Trascript score misZ 5.2832 (greater than threshold 3.09). GenCC has associacion of gene with developmental and epileptic encephalopathy, 58, undetermined early-onset epileptic encephalopathy, West syndrome, obesity, hyperphagia, and developmental delay.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 9-84955510-A-G is Pathogenic according to our data. Variant chr9-84955510-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 9127.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NTRK2	NM_006180.6	c.2165A>G	p.Tyr722Cys	missense_variant	17/19	ENST00000277120.8	NP_006171.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NTRK2	ENST00000277120.8	c.2165A>G	p.Tyr722Cys	missense_variant	17/19	1	NM_006180.6	ENSP00000277120	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Obesity, hyperphagia, and developmental delay Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	.;D;.;D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;.;.
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Uncertain	2.8	.;M;.;M
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-7.4	D;D;D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.97
MutPred		0.89		.;Loss of phosphorylation at Y706 (P = 0.0282);.;Loss of phosphorylation at Y706 (P = 0.0282);
MVP		0.96
MPC		2.8
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.94
gMVP		0.98

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: rs121434633; hg19: chr9-87570425;