rs2289658

chr9-84948455-T-C

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.1765-7T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0495 in 1,613,678 control chromosomes in the GnomAD database, including 2,691 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (299 hom., cov: 32)
  • Exomes 𝑓: 0.049 (2392 hom.)
• Consequence: NTRK2 NM_006180.6 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001185
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.818

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=-0.87).
• BP6: Variant 9-84948455-T-C is Benign according to our data. Variant chr9-84948455-T-C is described in ClinVar as [Benign]. Clinvar id is 1279330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NTRK2	NM_006180.6	c.1765-7T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000277120.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NTRK2	ENST00000277120.8	c.1765-7T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_006180.6	P3

Frequencies

GnomAD3 genomes AF: 0.0531 AC: 8076 AN: 152066 Hom.: 297 Cov.: 32

Gnomad AFR AF: 0.0483

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.0251

Gnomad EAS AF: 0.127

Gnomad SAS AF: 0.0641

Gnomad FIN AF: 0.0180

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0428

Gnomad OTH AF: 0.0556

GnomAD3 exomes AF: 0.0652 AC: 16342 AN: 250804 Hom.: 906 AF XY: 0.0605 AC XY: 8199 AN XY: 135626

Gnomad AFR exome AF: 0.0488

Gnomad AMR exome AF: 0.171

Gnomad ASJ exome AF: 0.0215

Gnomad EAS exome AF: 0.124

Gnomad SAS exome AF: 0.0549

Gnomad FIN exome AF: 0.0174

Gnomad NFE exome AF: 0.0421

Gnomad OTH exome AF: 0.0575

GnomAD4 exome AF: 0.0491 AC: 71787 AN: 1461494 Hom.: 2392 Cov.: 32 AF XY: 0.0485 AC XY: 35256 AN XY: 727052

Gnomad4 AFR exome AF: 0.0450

Gnomad4 AMR exome AF: 0.166

Gnomad4 ASJ exome AF: 0.0217

Gnomad4 EAS exome AF: 0.120

Gnomad4 SAS exome AF: 0.0517

Gnomad4 FIN exome AF: 0.0165

Gnomad4 NFE exome AF: 0.0439

Gnomad4 OTH exome AF: 0.0527

GnomAD4 genome AF: 0.0531 AC: 8083 AN: 152184 Hom.: 299 Cov.: 32 AF XY: 0.0534 AC XY: 3977 AN XY: 74416

Gnomad4 AFR AF: 0.0483

Gnomad4 AMR AF: 0.116

Gnomad4 ASJ AF: 0.0251

Gnomad4 EAS AF: 0.127

Gnomad4 SAS AF: 0.0635

Gnomad4 FIN AF: 0.0180

Gnomad4 NFE AF: 0.0429

Gnomad4 OTH AF: 0.0569

Alfa AF: 0.0464 Hom.: 374

Bravo AF: 0.0616

Asia WGS AF: 0.118 AC: 411 AN: 3478

EpiCase AF: 0.0439

EpiControl AF: 0.0412

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.66
Dann	Benign	0.44

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.022
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: rs2289658; hg19: chr9-87563370; COSMIC: COSV52855679;