NM_006180.6:c.583+3192T>A

Variant names:

• chr9-84713983-T-A
• rs10081630
• NM_006180.6:c.583+3192T>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.583+3192T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.091 in 152,088 control chromosomes in the GnomAD database, including 1,121 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 0.091 (1121 hom., cov: 32)
• Consequence: NTRK2 NM_006180.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.05
• Publications: 0 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.208 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.583+3192T>A		intron	N/A	NP_006171.2
	NTRK2	NM_001018064.3		c.583+3192T>A		intron	N/A	NP_001018074.1
	NTRK2	NM_001369532.1		c.583+3192T>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.583+3192T>A		intron	N/A	ENSP00000277120.3
	NTRK2	ENST00000323115.11	TSL:1	c.583+3192T>A		intron	N/A	ENSP00000314586.5
	NTRK2	ENST00000304053.11	TSL:1	c.583+3192T>A		intron	N/A	ENSP00000306167.7

Frequencies

GnomAD3 genomes AF: 0.0907 AC: 13788 AN: 151970 Hom.: 1109 Cov.: 32

Gnomad AFR AF: 0.211

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.0777

Gnomad ASJ AF: 0.0233

Gnomad EAS AF: 0.118

Gnomad SAS AF: 0.0341

Gnomad FIN AF: 0.0343

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0352

Gnomad OTH AF: 0.0675

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

GnomAD4 genome AF: 0.0910 AC: 13845 AN: 152088 Hom.: 1121 Cov.: 32 AF XY: 0.0895 AC XY: 6656 AN XY: 74384

African (AFR) AF: 0.212 AC: 8777 AN: 41416

American (AMR) AF: 0.0774 AC: 1184 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0233 AC: 81 AN: 3470

East Asian (EAS) AF: 0.118 AC: 610 AN: 5166

South Asian (SAS) AF: 0.0340 AC: 164 AN: 4828

European-Finnish (FIN) AF: 0.0343 AC: 364 AN: 10606

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0352 AC: 2392 AN: 67996

Other (OTH) AF: 0.0743 AC: 157 AN: 2112

Alfa AF: 0.0716 Hom.: 79

Bravo AF: 0.102

Asia WGS AF: 0.0990 AC: 343 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.38
DANN	Benign	0.16
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs10081630; hg19: chr9-87328898;