rs10868235

Variant names:

• chr9-84878840-C-T
• rs10868235
• NM_006180.6:c.1633+11409C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006180.6(NTRK2):​c.1633+11409C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.402 in 151,880 control chromosomes in the GnomAD database, including 13,888 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.40 (13888 hom., cov: 31)
• Consequence: NTRK2 NM_006180.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.417
• Publications: 27 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: Labcorp Genetics (formerly Invitae), G2P
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.516 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006180.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTRK2	NM_006180.6	MANE Select	c.1633+11409C>T		intron	N/A	NP_006171.2
	NTRK2	NM_001018064.3		c.1585+11409C>T		intron	N/A	NP_001018074.1	Q548C2
	NTRK2	NM_001369532.1		c.1585+11409C>T		intron	N/A	NP_001356461.1	Q16620-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTRK2	ENST00000277120.8	TSL:1 MANE Select	c.1633+11409C>T		intron	N/A	ENSP00000277120.3	Q16620-4
	NTRK2	ENST00000323115.11	TSL:1	c.1549+11409C>T		intron	N/A	ENSP00000314586.5	A0A8J8YUT9
	NTRK2	ENST00000686324.1		c.1633+11409C>T		intron	N/A	ENSP00000510134.1	Q16620-4

Frequencies

GnomAD3 genomes AF: 0.402 AC: 60993 AN: 151762 Hom.: 13886 Cov.: 31

Gnomad AFR AF: 0.184

Gnomad AMI AF: 0.452

Gnomad AMR AF: 0.418

Gnomad ASJ AF: 0.461

Gnomad EAS AF: 0.276

Gnomad SAS AF: 0.515

Gnomad FIN AF: 0.446

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.521

Gnomad OTH AF: 0.428

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.402 AC: 61010 AN: 151880 Hom.: 13888 Cov.: 31 AF XY: 0.400 AC XY: 29682 AN XY: 74224

African (AFR) AF: 0.184 AC: 7620 AN: 41436

American (AMR) AF: 0.419 AC: 6396 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 1599 AN: 3468

East Asian (EAS) AF: 0.275 AC: 1413 AN: 5144

South Asian (SAS) AF: 0.515 AC: 2476 AN: 4804

European-Finnish (FIN) AF: 0.446 AC: 4690 AN: 10510

Middle Eastern (MID) AF: 0.418 AC: 122 AN: 292

European-Non Finnish (NFE) AF: 0.521 AC: 35385 AN: 67938

Other (OTH) AF: 0.426 AC: 897 AN: 2108

Alfa AF: 0.464 Hom.: 11953

Bravo AF: 0.389

Asia WGS AF: 0.355 AC: 1236 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	7.8
DANN	Benign	0.56
PhyloP100		0.42
Mutation Taster		=100/0	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: rs10868235; hg19: chr9-87493755; COSMIC: COSV99452069;