ENST00000304053.11:c.*3053G>C

Variant names:

• chr9-84874870-G-C
• rs9969765
• ENST00000304053.11:c.*3053G>C

Variant summary

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

The ENST00000304053.11(NTRK2):​c.*3053G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.355 in 1,056,410 control chromosomes in the GnomAD database, including 67,792 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 0.41 (12837 hom., cov: 32)
  • Exomes 𝑓: 0.35 (54955 hom.)
• Consequence: NTRK2 ENST00000304053.11 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.18
• Publications: 9 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.495 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTRK2	NM_006180.6	c.1633+7439G>C		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+7439G>C		intron_variant	Intron 14 of 18	1	NM_006180.6	ENSP00000277120.3

Frequencies

GnomAD3 genomes AF: 0.405 AC: 61555 AN: 151882 Hom.: 12817 Cov.: 32

Gnomad AFR AF: 0.501

Gnomad AMI AF: 0.467

Gnomad AMR AF: 0.438

Gnomad ASJ AF: 0.355

Gnomad EAS AF: 0.467

Gnomad SAS AF: 0.371

Gnomad FIN AF: 0.376

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.344

Gnomad OTH AF: 0.399

GnomAD4 exome AF: 0.347 AC: 313613 AN: 904410 Hom.: 54955 Cov.: 31 AF XY: 0.346 AC XY: 144501 AN XY: 417690

African (AFR) AF: 0.502 AC: 9590 AN: 19116

American (AMR) AF: 0.417 AC: 1320 AN: 3166

Ashkenazi Jewish (ASJ) AF: 0.357 AC: 3470 AN: 9712

East Asian (EAS) AF: 0.516 AC: 7136 AN: 13834

South Asian (SAS) AF: 0.361 AC: 6156 AN: 17044

European-Finnish (FIN) AF: 0.338 AC: 108 AN: 320

Middle Eastern (MID) AF: 0.340 AC: 704 AN: 2070

European-Non Finnish (NFE) AF: 0.339 AC: 272783 AN: 805830

Other (OTH) AF: 0.371 AC: 12346 AN: 33318

GnomAD4 genome AF: 0.405 AC: 61617 AN: 152000 Hom.: 12837 Cov.: 32 AF XY: 0.408 AC XY: 30289 AN XY: 74322

African (AFR) AF: 0.501 AC: 20746 AN: 41428

American (AMR) AF: 0.437 AC: 6682 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.355 AC: 1230 AN: 3468

East Asian (EAS) AF: 0.468 AC: 2418 AN: 5166

South Asian (SAS) AF: 0.370 AC: 1787 AN: 4824

European-Finnish (FIN) AF: 0.376 AC: 3971 AN: 10572

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.344 AC: 23406 AN: 67948

Other (OTH) AF: 0.403 AC: 852 AN: 2112

Alfa AF: 0.376 Hom.: 1372

Bravo AF: 0.415

Asia WGS AF: 0.465 AC: 1617 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.46
DANN	Benign	0.42
PhyloP100		-1.2
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: rs9969765; hg19: chr9-87489785;