rs2289656

Variant names:

• chr9-84948647-G-A
• rs2289656
• NM_006180.6:c.1937+13G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-84948647-G-A
• chr9-84948647-G-C
• chr9-84948647-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006180.6(NTRK2):​c.1937+13G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 1,612,644 control chromosomes in the GnomAD database, including 24,178 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1953 hom., cov: 32)
  • Exomes 𝑓: 0.17 (22225 hom.)
• Consequence: NTRK2 NM_006180.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.26
• Publications: 36 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 9-84948647-G-A is Benign according to our data. Variant chr9-84948647-G-A is described in ClinVar as Benign. ClinVar VariationId is 1249612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTRK2	NM_006180.6	c.1937+13G>A		intron_variant	Intron 16 of 18	ENST00000277120.8	NP_006171.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTRK2	ENST00000277120.8	c.1937+13G>A		intron_variant	Intron 16 of 18	1	NM_006180.6	ENSP00000277120.3

Frequencies

GnomAD3 genomes AF: 0.153 AC: 23329 AN: 152072 Hom.: 1956 Cov.: 32

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.186

Gnomad AMR AF: 0.148

Gnomad ASJ AF: 0.248

Gnomad EAS AF: 0.0351

Gnomad SAS AF: 0.0913

Gnomad FIN AF: 0.171

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.185

Gnomad OTH AF: 0.164

GnomAD2 exomes AF: 0.150 AC: 37451 AN: 249854 AF XY: 0.151

Gnomad AFR exome AF: 0.109

Gnomad AMR exome AF: 0.125

Gnomad ASJ exome AF: 0.246

Gnomad EAS exome AF: 0.0332

Gnomad FIN exome AF: 0.166

Gnomad NFE exome AF: 0.183

Gnomad OTH exome AF: 0.172

GnomAD4 exome AF: 0.170 AC: 247774 AN: 1460454 Hom.: 22225 Cov.: 33 AF XY: 0.169 AC XY: 122517 AN XY: 726502

African (AFR) AF: 0.109 AC: 3643 AN: 33464

American (AMR) AF: 0.127 AC: 5668 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.242 AC: 6337 AN: 26134

East Asian (EAS) AF: 0.0378 AC: 1500 AN: 39694

South Asian (SAS) AF: 0.103 AC: 8877 AN: 86168

European-Finnish (FIN) AF: 0.162 AC: 8619 AN: 53368

Middle Eastern (MID) AF: 0.220 AC: 1269 AN: 5764

European-Non Finnish (NFE) AF: 0.182 AC: 201931 AN: 1110856

Other (OTH) AF: 0.165 AC: 9930 AN: 60338

GnomAD4 genome AF: 0.153 AC: 23328 AN: 152190 Hom.: 1953 Cov.: 32 AF XY: 0.151 AC XY: 11241 AN XY: 74392

African (AFR) AF: 0.111 AC: 4602 AN: 41524

American (AMR) AF: 0.148 AC: 2257 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.248 AC: 860 AN: 3470

East Asian (EAS) AF: 0.0354 AC: 183 AN: 5176

South Asian (SAS) AF: 0.0916 AC: 441 AN: 4816

European-Finnish (FIN) AF: 0.171 AC: 1812 AN: 10596

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.185 AC: 12593 AN: 67992

Other (OTH) AF: 0.164 AC: 346 AN: 2116

Alfa AF: 0.172 Hom.: 6847

Bravo AF: 0.150

Asia WGS AF: 0.0910 AC: 319 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Sep 25, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy, 58 Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Obesity, hyperphagia, and developmental delay Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.096
DANN	Benign	0.59
PhyloP100		-2.3
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: rs2289656; hg19: chr9-87563562; COSMIC: COSV52852599;