chr9-84980801-G-A

Variant names:

• chr9-84980801-G-A
• rs10746752
• NM_006180.6:c.2172+25284G>A

Variant summary

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

The NM_006180.6(NTRK2):​c.2172+25284G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0987 in 152,274 control chromosomes in the GnomAD database, including 1,156 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 0.099 (1156 hom., cov: 33)
• Consequence: NTRK2 NM_006180.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.362
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.425 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTRK2	NM_006180.6	MANE Select	c.2172+25284G>A		intron	N/A	NP_006171.2
	NTRK2	NM_001018064.3		c.2124+25284G>A		intron	N/A	NP_001018074.1
	NTRK2	NM_001369532.1		c.2124+25284G>A		intron	N/A	NP_001356461.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTRK2	ENST00000277120.8	TSL:1 MANE Select	c.2172+25284G>A		intron	N/A	ENSP00000277120.3
	NTRK2	ENST00000323115.11	TSL:1	c.2088+25284G>A		intron	N/A	ENSP00000314586.5
	NTRK2	ENST00000686324.1		c.2172+25284G>A		intron	N/A	ENSP00000510134.1

Frequencies

GnomAD3 genomes AF: 0.0987 AC: 15018 AN: 152156 Hom.: 1154 Cov.: 33

Gnomad AFR AF: 0.0617

Gnomad AMI AF: 0.117

Gnomad AMR AF: 0.138

Gnomad ASJ AF: 0.0458

Gnomad EAS AF: 0.439

Gnomad SAS AF: 0.0993

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0882

Gnomad OTH AF: 0.0893

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

GnomAD4 genome AF: 0.0987 AC: 15027 AN: 152274 Hom.: 1156 Cov.: 33 AF XY: 0.102 AC XY: 7602 AN XY: 74460

African (AFR) AF: 0.0615 AC: 2558 AN: 41576

American (AMR) AF: 0.137 AC: 2102 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0458 AC: 159 AN: 3468

East Asian (EAS) AF: 0.441 AC: 2274 AN: 5162

South Asian (SAS) AF: 0.0996 AC: 481 AN: 4830

European-Finnish (FIN) AF: 0.107 AC: 1133 AN: 10608

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0882 AC: 6001 AN: 68016

Other (OTH) AF: 0.0893 AC: 189 AN: 2116

Alfa AF: 0.0941 Hom.: 393

Bravo AF: 0.103

Asia WGS AF: 0.230 AC: 801 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.60
DANN	Benign	0.67
PhyloP100		-0.36
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: rs10746752; hg19: chr9-87595716; COSMIC: COSV52858271;