chr9-84876565-A-C

Variant names:

• chr9-84876565-A-C
• rs11140793
• ENST00000304053.11:c.*4748A>C

Variant summary

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

The ENST00000304053.11(NTRK2):​c.*4748A>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 0.169 in 1,056,196 control chromosomes in the GnomAD database, including 15,590 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 (2718 hom., cov: 32)
  • Exomes 𝑓: 0.17 (12872 hom.)
• Consequence: NTRK2 ENST00000304053.11 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.117
• Publications: 12 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.244 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000304053.11. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTRK2	NM_006180.6	MANE Select	c.1633+9134A>C		intron	N/A	NP_006171.2
	NTRK2	NM_001018065.2		c.*4748A>C		3_prime_UTR	Exon 15 of 15	NP_001018075.1
	NTRK2	NM_001369537.1		c.*4748A>C		3_prime_UTR	Exon 16 of 16	NP_001356466.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTRK2	ENST00000304053.11	TSL:1	c.*4748A>C		3_prime_UTR	Exon 13 of 13	ENSP00000306167.7
	NTRK2	ENST00000376208.6	TSL:1	c.*4748A>C		3_prime_UTR	Exon 16 of 16	ENSP00000365381.1
	NTRK2	ENST00000277120.8	TSL:1 MANE Select	c.1633+9134A>C		intron	N/A	ENSP00000277120.3

Frequencies

GnomAD3 genomes AF: 0.183 AC: 27787 AN: 152100 Hom.: 2715 Cov.: 32

Gnomad AFR AF: 0.248

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.198

Gnomad ASJ AF: 0.156

Gnomad EAS AF: 0.0500

Gnomad SAS AF: 0.151

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.143

Gnomad NFE AF: 0.163

Gnomad OTH AF: 0.185

GnomAD4 exome AF: 0.167 AC: 150628 AN: 903978 Hom.: 12872 Cov.: 31 AF XY: 0.166 AC XY: 69444 AN XY: 417496

African (AFR) AF: 0.248 AC: 4740 AN: 19146

American (AMR) AF: 0.168 AC: 528 AN: 3152

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 1513 AN: 9696

East Asian (EAS) AF: 0.0385 AC: 528 AN: 13720

South Asian (SAS) AF: 0.157 AC: 2688 AN: 17076

European-Finnish (FIN) AF: 0.120 AC: 39 AN: 326

Middle Eastern (MID) AF: 0.130 AC: 267 AN: 2060

European-Non Finnish (NFE) AF: 0.167 AC: 134547 AN: 805554

Other (OTH) AF: 0.174 AC: 5778 AN: 33248

GnomAD4 genome AF: 0.183 AC: 27813 AN: 152218 Hom.: 2718 Cov.: 32 AF XY: 0.180 AC XY: 13436 AN XY: 74452

African (AFR) AF: 0.248 AC: 10285 AN: 41522

American (AMR) AF: 0.197 AC: 3019 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 540 AN: 3466

East Asian (EAS) AF: 0.0503 AC: 261 AN: 5184

South Asian (SAS) AF: 0.151 AC: 727 AN: 4822

European-Finnish (FIN) AF: 0.127 AC: 1345 AN: 10624

Middle Eastern (MID) AF: 0.137 AC: 40 AN: 292

European-Non Finnish (NFE) AF: 0.163 AC: 11068 AN: 67990

Other (OTH) AF: 0.183 AC: 387 AN: 2114

Alfa AF: 0.143 Hom.: 850

Bravo AF: 0.189

Asia WGS AF: 0.104 AC: 361 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.73
DANN	Benign	0.53
PhyloP100		-0.12
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: rs11140793; hg19: chr9-87491480;