rs1085308029

Variant names:

• chr9-84752019-G-A
• rs1085308029
• NM_006180.6:c.1330G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-84752019-G-A
• chr9-84752019-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006180.6(NTRK2):​c.1330G>A​(p.Gly444Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G444G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NTRK2 NM_006180.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.01
• Publications: 0 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 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
NTRK2	NM_006180.6	c.1330G>A	p.Gly444Arg	missense_variant	Exon 12 of 19	ENST00000277120.8	NP_006171.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTRK2	ENST00000277120.8	c.1330G>A	p.Gly444Arg	missense_variant	Exon 12 of 19	1	NM_006180.6	ENSP00000277120.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Mar 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 444 of the NTRK2 protein (p.Gly444Arg). 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. 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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	.;D;.;.;.;.;D;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;.;.;.
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.52	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	1.0	L;L;L;L;L;L;L;L
PhyloP100		4.0
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.0	N;N;N;N;N;N;N;N
REVEL	Uncertain	0.50
Sift	Benign	0.059	T;T;D;T;T;T;T;D
Sift4G	Benign	0.36	T;T;T;T;T;T;T;T
Polyphen		0.94	P;B;D;D;D;P;B;D
Vest4		0.62
MutPred		0.70		Gain of MoRF binding (P = 0.0221);Gain of MoRF binding (P = 0.0221);Gain of MoRF binding (P = 0.0221);Gain of MoRF binding (P = 0.0221);Gain of MoRF binding (P = 0.0221);Gain of MoRF binding (P = 0.0221);Gain of MoRF binding (P = 0.0221);Gain of MoRF binding (P = 0.0221);
MVP		0.97
MPC		1.8
ClinPred		0.88	D
GERP RS		5.2
Varity_R		0.21
gMVP		0.92
Mutation Taster		=49/51	disease causing

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: rs1085308029; hg19: chr9-87366934;