rs10780691

Variant names:

• chr9-84876338-C-T
• rs10780691
• ENST00000304053.11:c.*4521C>T

Variant summary

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

The ENST00000304053.11(NTRK2):​c.*4521C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.482 in 1,049,362 control chromosomes in the GnomAD database, including 126,204 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 0.39 (13186 hom., cov: 32)
  • Exomes 𝑓: 0.50 (113018 hom.)
• Consequence: NTRK2 ENST00000304053.11 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.602
• Publications: 16 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=-0.88).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.501 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTRK2	NM_006180.6	c.1633+8907C>T		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+8907C>T		intron_variant	Intron 14 of 18	1	NM_006180.6	ENSP00000277120.3

Frequencies

GnomAD3 genomes AF: 0.392 AC: 59580 AN: 151910 Hom.: 13183 Cov.: 32

Gnomad AFR AF: 0.181

Gnomad AMI AF: 0.431

Gnomad AMR AF: 0.407

Gnomad ASJ AF: 0.456

Gnomad EAS AF: 0.263

Gnomad SAS AF: 0.517

Gnomad FIN AF: 0.445

Gnomad MID AF: 0.402

Gnomad NFE AF: 0.506

Gnomad OTH AF: 0.409

GnomAD4 exome AF: 0.497 AC: 446146 AN: 897334 Hom.: 113018 Cov.: 29 AF XY: 0.498 AC XY: 206380 AN XY: 414474

African (AFR) AF: 0.161 AC: 3037 AN: 18840

American (AMR) AF: 0.429 AC: 1255 AN: 2928

Ashkenazi Jewish (ASJ) AF: 0.438 AC: 4078 AN: 9302

East Asian (EAS) AF: 0.243 AC: 3223 AN: 13242

South Asian (SAS) AF: 0.525 AC: 8939 AN: 17012

European-Finnish (FIN) AF: 0.472 AC: 153 AN: 324

Middle Eastern (MID) AF: 0.464 AC: 941 AN: 2028

European-Non Finnish (NFE) AF: 0.511 AC: 409406 AN: 800976

Other (OTH) AF: 0.462 AC: 15114 AN: 32682

GnomAD4 genome AF: 0.392 AC: 59598 AN: 152028 Hom.: 13186 Cov.: 32 AF XY: 0.391 AC XY: 29019 AN XY: 74306

African (AFR) AF: 0.181 AC: 7506 AN: 41484

American (AMR) AF: 0.408 AC: 6235 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.456 AC: 1581 AN: 3468

East Asian (EAS) AF: 0.261 AC: 1354 AN: 5180

South Asian (SAS) AF: 0.518 AC: 2488 AN: 4806

European-Finnish (FIN) AF: 0.445 AC: 4692 AN: 10550

Middle Eastern (MID) AF: 0.412 AC: 121 AN: 294

European-Non Finnish (NFE) AF: 0.506 AC: 34370 AN: 67942

Other (OTH) AF: 0.407 AC: 859 AN: 2110

Alfa AF: 0.464 Hom.: 46913

Bravo AF: 0.378

Asia WGS AF: 0.352 AC: 1226 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.4
DANN	Benign	0.70
PhyloP100		-0.60
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: rs10780691; hg19: chr9-87491253;