9-84948455-T-C

Variant names:

• chr9-84948455-T-C
• rs2289658
• NM_006180.6:c.1765-7T>C

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.1765-7T>C variant causes a splice region, 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, intron
• Scores: Splicing: ADA: 0.0001185
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.818
• Publications: 21 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=-0.87).
• BP6: Variant 9-84948455-T-C is Benign according to our data. Variant chr9-84948455-T-C is described in ClinVar as Benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
NTRK2	NM_006180.6	c.1765-7T>C		splice_region_variant, intron_variant	Intron 15 of 18	ENST00000277120.8	NP_006171.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTRK2	ENST00000277120.8	c.1765-7T>C		splice_region_variant, intron_variant	Intron 15 of 18	1	NM_006180.6	ENSP00000277120.3

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

GnomAD2 exomes AF: 0.0652 AC: 16342 AN: 250804 AF XY: 0.0605

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 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

African (AFR) AF: 0.0450 AC: 1506 AN: 33476

American (AMR) AF: 0.166 AC: 7414 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.0217 AC: 567 AN: 26132

East Asian (EAS) AF: 0.120 AC: 4777 AN: 39690

South Asian (SAS) AF: 0.0517 AC: 4461 AN: 86224

European-Finnish (FIN) AF: 0.0165 AC: 883 AN: 53400

Middle Eastern (MID) AF: 0.0329 AC: 190 AN: 5768

European-Non Finnish (NFE) AF: 0.0439 AC: 48808 AN: 1111756

Other (OTH) AF: 0.0527 AC: 3181 AN: 60376

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

African (AFR) AF: 0.0483 AC: 2004 AN: 41524

American (AMR) AF: 0.116 AC: 1779 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0251 AC: 87 AN: 3472

East Asian (EAS) AF: 0.127 AC: 659 AN: 5170

South Asian (SAS) AF: 0.0635 AC: 306 AN: 4818

European-Finnish (FIN) AF: 0.0180 AC: 191 AN: 10604

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

European-Non Finnish (NFE) AF: 0.0429 AC: 2914 AN: 68004

Other (OTH) AF: 0.0569 AC: 120 AN: 2110

Alfa AF: 0.0484 Hom.: 847

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: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	-0.87
CADD	Benign	0.66
DANN	Benign	0.44
PhyloP100		-0.82
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2289658; hg19: chr9-87563370;