9-84670804-G-A

Position:

• chr9-84670804-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_006180.6(NTRK2):​c.56G>A​(p.Cys19Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,244 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: NTRK2 NM_006180.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.40

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NTRK2	NM_006180.6	c.56G>A	p.Cys19Tyr	missense_variant	2/19	ENST00000277120.8	NP_006171.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NTRK2	ENST00000277120.8	c.56G>A	p.Cys19Tyr	missense_variant	2/19	1	NM_006180.6	ENSP00000277120.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152244 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152244 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74388

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

NTRK2-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 18, 2022

The NTRK2 c.56G>A variant is predicted to result in the amino acid substitution p.Cys19Tyr. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Developmental and epileptic encephalopathy, 58 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Servicio de Genética Del Instituto Nacional de Salud Del Niño, Ministerio de Salud

Nov 18, 2024

The variant NM_006180.6:c.56G>A results in the substitution of cysteine with tyrosine at position 19 in the protein. Cysteine is a sulfur-containing amino acid, while tyrosine is aromatic and polar, which could potentially affect the protein's structure or function, particularly if the cysteine residue is involved in disulfide bonding. Based on PP2 (observed in a gene with a known functional effect) and PM2 (absence from controls or databases), this variant is classified as of uncertain significance (VUS). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.57	.;D;.;.;.;.;D;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.86	D;D;D;D;D;.;.;.
M_CAP	Benign	0.077	D
MetaRNN	Uncertain	0.59	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	0.97	L;L;L;L;L;L;L;L
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.6	D;D;D;D;D;D;D;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.023	D;D;D;D;D;D;D;D
Sift4G	Benign	0.44	T;T;T;T;T;T;T;T
Polyphen		0.85	P;P;D;P;P;P;P;D
Vest4		0.75
MutPred		0.39		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.89
MPC		2.2
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.53
gMVP		0.73

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: rs200698390; hg19: chr9-87285719; COSMIC: COSV99453259;