NM_006180.6:c.1634-18566T>C

Variant names:

• chr9-84915596-T-C
• rs4304401
• NM_006180.6:c.1634-18566T>C

Variant summary

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

The NM_006180.6(NTRK2):​c.1634-18566T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 152,134 control chromosomes in the GnomAD database, including 2,133 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 0.13 (2133 hom., cov: 32)
• Consequence: NTRK2 NM_006180.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.634
• 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=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.284 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTRK2	NM_006180.6	c.1634-18566T>C		intron_variant	Intron 14 of 18	ENST00000277120.8	NP_006171.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTRK2	ENST00000277120.8	c.1634-18566T>C		intron_variant	Intron 14 of 18	1	NM_006180.6	ENSP00000277120.3

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19632 AN: 152016 Hom.: 2125 Cov.: 32

Gnomad AFR AF: 0.289

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.0611

Gnomad EAS AF: 0.0639

Gnomad SAS AF: 0.0426

Gnomad FIN AF: 0.0235

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0583

Gnomad OTH AF: 0.120

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

GnomAD4 genome AF: 0.129 AC: 19677 AN: 152134 Hom.: 2133 Cov.: 32 AF XY: 0.127 AC XY: 9465 AN XY: 74396

African (AFR) AF: 0.289 AC: 11967 AN: 41456

American (AMR) AF: 0.161 AC: 2465 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0611 AC: 212 AN: 3470

East Asian (EAS) AF: 0.0641 AC: 331 AN: 5166

South Asian (SAS) AF: 0.0429 AC: 207 AN: 4828

European-Finnish (FIN) AF: 0.0235 AC: 249 AN: 10612

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0583 AC: 3966 AN: 68002

Other (OTH) AF: 0.119 AC: 251 AN: 2114

Alfa AF: 0.0884 Hom.: 1187

Bravo AF: 0.149

Asia WGS AF: 0.0830 AC: 287 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.8
DANN	Benign	0.46
PhyloP100		-0.63
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: rs4304401; hg19: chr9-87530511;