rs3780634

Variant names:

• chr9-84873803-A-G
• rs3780634
• ENST00000304053.11:c.*1986A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000304053.11(NTRK2):​c.*1986A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.169 in 1,056,366 control chromosomes in the GnomAD database, including 15,515 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.18 (2697 hom., cov: 32)
  • Exomes 𝑓: 0.17 (12818 hom.)
• Consequence: NTRK2 ENST00000304053.11 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.33
• Publications: 13 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.227 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTRK2	NM_006180.6	c.1633+6372A>G		intron_variant	Intron 14 of 18	ENST00000277120.8	NP_006171.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTRK2	ENST00000277120.8	c.1633+6372A>G		intron_variant	Intron 14 of 18	1	NM_006180.6	ENSP00000277120.3

Frequencies

GnomAD3 genomes AF: 0.182 AC: 27725 AN: 152056 Hom.: 2695 Cov.: 32

Gnomad AFR AF: 0.230

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.234

Gnomad ASJ AF: 0.156

Gnomad EAS AF: 0.0628

Gnomad SAS AF: 0.152

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.163

Gnomad OTH AF: 0.195

GnomAD4 exome AF: 0.166 AC: 150502 AN: 904192 Hom.: 12818 Cov.: 26 AF XY: 0.166 AC XY: 69396 AN XY: 417644

African (AFR) AF: 0.225 AC: 4323 AN: 19194

American (AMR) AF: 0.219 AC: 696 AN: 3182

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 1519 AN: 9718

East Asian (EAS) AF: 0.0652 AC: 915 AN: 14026

South Asian (SAS) AF: 0.158 AC: 2705 AN: 17076

European-Finnish (FIN) AF: 0.118 AC: 39 AN: 330

Middle Eastern (MID) AF: 0.128 AC: 265 AN: 2066

European-Non Finnish (NFE) AF: 0.167 AC: 134233 AN: 805322

Other (OTH) AF: 0.174 AC: 5807 AN: 33278

GnomAD4 genome AF: 0.182 AC: 27755 AN: 152174 Hom.: 2697 Cov.: 32 AF XY: 0.181 AC XY: 13477 AN XY: 74404

African (AFR) AF: 0.230 AC: 9561 AN: 41500

American (AMR) AF: 0.233 AC: 3567 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 543 AN: 3472

East Asian (EAS) AF: 0.0631 AC: 327 AN: 5182

South Asian (SAS) AF: 0.152 AC: 730 AN: 4808

European-Finnish (FIN) AF: 0.126 AC: 1341 AN: 10604

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.163 AC: 11096 AN: 68002

Other (OTH) AF: 0.193 AC: 408 AN: 2114

Alfa AF: 0.164 Hom.: 1990

Bravo AF: 0.191

Asia WGS AF: 0.115 AC: 400 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.0020
DANN	Benign	0.42
PhyloP100		-3.3
Mutation Taster		=100/0	polymorphism (auto)

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: rs3780634; hg19: chr9-87488718;