rs2289656

chr9-84948647-G-A

Variant summary

Our verdict is Benign. Variant got -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:4
• Conservation: PhyloP100: -2.26

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 -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 id 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/exons	MANE	UniProt
NTRK2	NM_006180.6	c.1937+13G>A		intron_variant		ENST00000277120.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NTRK2	ENST00000277120.8	c.1937+13G>A		intron_variant		1	NM_006180.6	P3

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

GnomAD3 exomes AF: 0.150 AC: 37451 AN: 249854 Hom.: 3174 AF XY: 0.151 AC XY: 20363 AN XY: 135024

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 SAS exome AF: 0.100

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

Gnomad4 AFR exome AF: 0.109

Gnomad4 AMR exome AF: 0.127

Gnomad4 ASJ exome AF: 0.242

Gnomad4 EAS exome AF: 0.0378

Gnomad4 SAS exome AF: 0.103

Gnomad4 FIN exome AF: 0.162

Gnomad4 NFE exome AF: 0.182

Gnomad4 OTH exome AF: 0.165

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

Gnomad4 AFR AF: 0.111

Gnomad4 AMR AF: 0.148

Gnomad4 ASJ AF: 0.248

Gnomad4 EAS AF: 0.0354

Gnomad4 SAS AF: 0.0916

Gnomad4 FIN AF: 0.171

Gnomad4 NFE AF: 0.185

Gnomad4 OTH AF: 0.164

Alfa AF: 0.182 Hom.: 2864

Bravo AF: 0.150

Asia WGS AF: 0.0910 AC: 319 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

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 25, 2018	- -

Obesity, hyperphagia, and developmental delay Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Developmental and epileptic encephalopathy, 58 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.096
Dann	Benign	0.59

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: rs2289656; hg19: chr9-87563562; COSMIC: COSV52852599;