rs2289657

chr9-84948545-C-Achr9-84948545-C-Gchr9-84948545-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_006180.6(NTRK2):c.1848C>A(p.Ile616=) 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:2
• Conservation: PhyloP100: -1.32

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	UniProt
NTRK2	NM_006180.6	c.1848C>A	p.Ile616=	synonymous_variant	16/19	ENST00000277120.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NTRK2	ENST00000277120.8	c.1848C>A	p.Ile616=	synonymous_variant	16/19	1	NM_006180.6	P3

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

GnomAD3 exomes AF: 0.0490 AC: 12311 AN: 251360 Hom.: 437 AF XY: 0.0461 AC XY: 6265 AN XY: 135854

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 SAS exome AF: 0.0319

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

Gnomad4 AFR exome AF: 0.0430

Gnomad4 AMR exome AF: 0.106

Gnomad4 ASJ exome AF: 0.0159

Gnomad4 EAS exome AF: 0.0650

Gnomad4 SAS exome AF: 0.0307

Gnomad4 FIN exome AF: 0.0165

Gnomad4 NFE exome AF: 0.0437

Gnomad4 OTH exome AF: 0.0452

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

Gnomad4 AFR AF: 0.0457

Gnomad4 AMR AF: 0.0773

Gnomad4 ASJ AF: 0.0210

Gnomad4 EAS AF: 0.0679

Gnomad4 SAS AF: 0.0376

Gnomad4 FIN AF: 0.0179

Gnomad4 NFE AF: 0.0426

Gnomad4 OTH AF: 0.0436

Alfa AF: 0.0325 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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
Cadd	Benign	1.3
Dann	Benign	0.81

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

Publications

LitVar

Other links and lift over

dbSNP: rs2289657; hg19: chr9-87563460; COSMIC: COSV52855698;