chr9-84727770-T-A

Variant names:

• chr9-84727770-T-A
• rs201362502
• NM_006180.6:c.970T>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006180.6(NTRK2):​c.970T>A​(p.Leu324Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as other (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NTRK2 NM_006180.6 missense
• Clinical Significance: other no assertion criteria provided O:1
• Conservation: PhyloP100: -0.899
• Publications: 1 publications found

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]

NTRK2 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 58

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• obesity, hyperphagia, and developmental delay

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30172718).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTRK2	NM_006180.6	c.970T>A	p.Leu324Met	missense_variant	Exon 9 of 19	ENST00000277120.8	NP_006171.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTRK2	ENST00000277120.8	c.970T>A	p.Leu324Met	missense_variant	Exon 9 of 19	1	NM_006180.6	ENSP00000277120.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: other

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Neuroblastoma Other:1

May 01, 2016

Donald Williams Parsons Laboratory, Baylor College of Medicine

Significance: other

Review Status: no assertion criteria provided

Collection Method: clinical testing

- 2: Mutations in members of targetable cancer pathways, gene families, or functional groups, regardless of tumor type;

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	.;D;.;.;.;.;D;.
Eigen	Benign	0.070
Eigen_PC	Benign	-0.087
FATHMM_MKL	Benign	0.11	N
LIST_S2	Uncertain	0.90	D;D;D;D;D;.;.;.
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.30	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.35	T
MutationAssessor	Uncertain	2.7	M;M;M;M;M;M;M;M
PhyloP100		-0.90
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.1	N;N;N;N;N;N;N;N
REVEL	Uncertain	0.39
Sift	Uncertain	0.0020	D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.022	D;D;D;D;D;D;D;D
Polyphen		0.99	D;D;D;D;D;D;D;D
Vest4		0.42
MutPred		0.37		Loss of catalytic residue at L324 (P = 0.0395);Loss of catalytic residue at L324 (P = 0.0395);Loss of catalytic residue at L324 (P = 0.0395);Loss of catalytic residue at L324 (P = 0.0395);Loss of catalytic residue at L324 (P = 0.0395);Loss of catalytic residue at L324 (P = 0.0395);Loss of catalytic residue at L324 (P = 0.0395);Loss of catalytic residue at L324 (P = 0.0395);
MVP		0.72
MPC		1.7
ClinPred		0.79	D
GERP RS		-0.83
Varity_R		0.75
gMVP		0.89
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

dbSNP: rs201362502; hg19: chr9-87342685;