9-84777667-C-T

Variant names:

• chr9-84777667-C-T
• rs10465180
• NM_006180.6:c.1396+25582C>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.1396+25582C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.618 in 151,910 control chromosomes in the GnomAD database, including 29,617 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 0.62 (29617 hom., cov: 32)
• Consequence: NTRK2 NM_006180.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.833
• Publications: 7 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=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.664 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.1396+25582C>T		intron	N/A	NP_006171.2
	NTRK2	NM_001018064.3		c.1396+25582C>T		intron	N/A	NP_001018074.1	Q548C2
	NTRK2	NM_001369532.1		c.1396+25582C>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.1396+25582C>T		intron	N/A	ENSP00000277120.3	Q16620-4
	NTRK2	ENST00000323115.11	TSL:1	c.1360+25582C>T		intron	N/A	ENSP00000314586.5	A0A8J8YUT9
	NTRK2	ENST00000304053.11	TSL:1	c.1396+25582C>T		intron	N/A	ENSP00000306167.7	Q16620-3

Frequencies

GnomAD3 genomes AF: 0.618 AC: 93827 AN: 151792 Hom.: 29629 Cov.: 32

Gnomad AFR AF: 0.497

Gnomad AMI AF: 0.564

Gnomad AMR AF: 0.628

Gnomad ASJ AF: 0.659

Gnomad EAS AF: 0.679

Gnomad SAS AF: 0.684

Gnomad FIN AF: 0.727

Gnomad MID AF: 0.586

Gnomad NFE AF: 0.662

Gnomad OTH AF: 0.626

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

GnomAD4 genome AF: 0.618 AC: 93840 AN: 151910 Hom.: 29617 Cov.: 32 AF XY: 0.621 AC XY: 46129 AN XY: 74252

African (AFR) AF: 0.496 AC: 20554 AN: 41406

American (AMR) AF: 0.629 AC: 9598 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.659 AC: 2285 AN: 3470

East Asian (EAS) AF: 0.679 AC: 3489 AN: 5138

South Asian (SAS) AF: 0.683 AC: 3289 AN: 4814

European-Finnish (FIN) AF: 0.727 AC: 7679 AN: 10560

Middle Eastern (MID) AF: 0.575 AC: 168 AN: 292

European-Non Finnish (NFE) AF: 0.662 AC: 44964 AN: 67950

Other (OTH) AF: 0.618 AC: 1303 AN: 2108

Alfa AF: 0.645 Hom.: 77568

Bravo AF: 0.602

Asia WGS AF: 0.628 AC: 2183 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.63
DANN	Benign	0.62
PhyloP100		-0.83
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: rs10465180; hg19: chr9-87392582;