9-84727770-T-A

Position:

• chr9-84727770-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The ENST00000277120.8(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 ENST00000277120.8 missense
• Clinical Significance: other no assertion criteria provided O:1
• Conservation: PhyloP100: -0.899

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 Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NTRK2	NM_006180.6	c.970T>A	p.Leu324Met	missense_variant	9/19	ENST00000277120.8	NP_006171.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NTRK2	ENST00000277120.8	c.970T>A	p.Leu324Met	missense_variant	9/19	1	NM_006180.6	ENSP00000277120	P3

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

other, no assertion criteria provided

clinical testing

Donald Williams Parsons Laboratory, Baylor College of Medicine

May 01, 2016

- 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
MutationTaster	Benign	0.95	N;N;N;N;N;N;N;N;N
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

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: rs201362502; hg19: chr9-87342685; COSMIC: COSV52854023;