rs2289657

Variant names:

• chr9-84948545-C-A
• rs2289657
• NM_006180.6:c.1848C>A

Your query was ambiguous. Multiple possible variants found:

• chr9-84948545-C-A
• chr9-84948545-C-G
• chr9-84948545-C-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_006180.6(NTRK2):​c.1848C>A​(p.Ile616Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0441 in 1,614,016 control chromosomes in the GnomAD database, including 1,839 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. I616I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.045 (196 hom., cov: 32)
  • Exomes 𝑓: 0.044 (1643 hom.)
• Consequence: NTRK2 NM_006180.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.32
• Publications: 22 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BP6: Variant 9-84948545-C-A is Benign according to our data. Variant chr9-84948545-C-A is described in ClinVar as Benign. ClinVar VariationId is 1268912.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.32 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0737 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTRK2	NM_006180.6	c.1848C>A	p.Ile616Ile	synonymous_variant	Exon 16 of 19	ENST00000277120.8	NP_006171.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTRK2	ENST00000277120.8	c.1848C>A	p.Ile616Ile	synonymous_variant	Exon 16 of 19	1	NM_006180.6	ENSP00000277120.3

Frequencies

GnomAD3 genomes AF: 0.0453 AC: 6884 AN: 152068 Hom.: 195 Cov.: 32

Gnomad AFR AF: 0.0458

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0773

Gnomad ASJ AF: 0.0210

Gnomad EAS AF: 0.0675

Gnomad SAS AF: 0.0380

Gnomad FIN AF: 0.0179

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0426

Gnomad OTH AF: 0.0440

GnomAD2 exomes AF: 0.0490 AC: 12311 AN: 251360 AF XY: 0.0461

Gnomad AFR exome AF: 0.0467

Gnomad AMR exome AF: 0.109

Gnomad ASJ exome AF: 0.0153

Gnomad EAS exome AF: 0.0678

Gnomad FIN exome AF: 0.0174

Gnomad NFE exome AF: 0.0418

Gnomad OTH exome AF: 0.0462

GnomAD4 exome AF: 0.0440 AC: 64270 AN: 1461830 Hom.: 1643 Cov.: 32 AF XY: 0.0432 AC XY: 31387 AN XY: 727212

African (AFR) AF: 0.0430 AC: 1440 AN: 33480

American (AMR) AF: 0.106 AC: 4754 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0159 AC: 415 AN: 26136

East Asian (EAS) AF: 0.0650 AC: 2581 AN: 39700

South Asian (SAS) AF: 0.0307 AC: 2648 AN: 86248

European-Finnish (FIN) AF: 0.0165 AC: 882 AN: 53416

Middle Eastern (MID) AF: 0.0312 AC: 180 AN: 5768

European-Non Finnish (NFE) AF: 0.0437 AC: 48640 AN: 1111970

Other (OTH) AF: 0.0452 AC: 2730 AN: 60394

GnomAD4 genome AF: 0.0452 AC: 6885 AN: 152186 Hom.: 196 Cov.: 32 AF XY: 0.0445 AC XY: 3312 AN XY: 74398

African (AFR) AF: 0.0457 AC: 1900 AN: 41536

American (AMR) AF: 0.0773 AC: 1182 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0210 AC: 73 AN: 3468

East Asian (EAS) AF: 0.0679 AC: 350 AN: 5156

South Asian (SAS) AF: 0.0376 AC: 181 AN: 4810

European-Finnish (FIN) AF: 0.0179 AC: 190 AN: 10610

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0426 AC: 2894 AN: 68004

Other (OTH) AF: 0.0436 AC: 92 AN: 2112

Alfa AF: 0.0327 Hom.: 45

Bravo AF: 0.0506

Asia WGS AF: 0.0680 AC: 236 AN: 3478

EpiCase AF: 0.0436

EpiControl AF: 0.0408

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 04, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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	-0.25
CADD	Benign	1.3
DANN	Benign	0.81
PhyloP100		-1.3
Mutation Taster		=91/9	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: rs2289657; hg19: chr9-87563460; COSMIC: COSV52855698;