9-84737873-C-T

Variant names:

• chr9-84737873-C-T
• rs3780632
• NM_006180.6:c.1160-4019C>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.1160-4019C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.587 in 151,100 control chromosomes in the GnomAD database, including 27,800 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 0.59 (27800 hom., cov: 30)
• Consequence: NTRK2 NM_006180.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.06
• Publications: 2 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=-0.87).
• 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTRK2	NM_006180.6	MANE Select	c.1160-4019C>T		intron	N/A	NP_006171.2
	NTRK2	NM_001018064.3		c.1160-4019C>T		intron	N/A	NP_001018074.1
	NTRK2	NM_001369532.1		c.1160-4019C>T		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.1160-4019C>T		intron	N/A	ENSP00000277120.3
	NTRK2	ENST00000323115.11	TSL:1	c.1160-7100C>T		intron	N/A	ENSP00000314586.5
	NTRK2	ENST00000304053.11	TSL:1	c.1160-4019C>T		intron	N/A	ENSP00000306167.7

Frequencies

GnomAD3 genomes AF: 0.587 AC: 88655 AN: 150982 Hom.: 27817 Cov.: 30

Gnomad AFR AF: 0.383

Gnomad AMI AF: 0.568

Gnomad AMR AF: 0.618

Gnomad ASJ AF: 0.662

Gnomad EAS AF: 0.676

Gnomad SAS AF: 0.685

Gnomad FIN AF: 0.727

Gnomad MID AF: 0.580

Gnomad NFE AF: 0.663

Gnomad OTH AF: 0.607

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

GnomAD4 genome AF: 0.587 AC: 88646 AN: 151100 Hom.: 27800 Cov.: 30 AF XY: 0.592 AC XY: 43699 AN XY: 73842

African (AFR) AF: 0.382 AC: 15525 AN: 40636

American (AMR) AF: 0.618 AC: 9419 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.662 AC: 2294 AN: 3466

East Asian (EAS) AF: 0.676 AC: 3483 AN: 5152

South Asian (SAS) AF: 0.684 AC: 3286 AN: 4806

European-Finnish (FIN) AF: 0.727 AC: 7646 AN: 10512

Middle Eastern (MID) AF: 0.568 AC: 166 AN: 292

European-Non Finnish (NFE) AF: 0.663 AC: 45048 AN: 67982

Other (OTH) AF: 0.600 AC: 1261 AN: 2102

Alfa AF: 0.634 Hom.: 31455

Bravo AF: 0.565

Asia WGS AF: 0.618 AC: 2150 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.3
DANN	Benign	0.58
PhyloP100		-1.1
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: rs3780632; hg19: chr9-87352788;