rs4242630

Variant names:

• chr9-84996630-C-T
• rs4242630
• NM_006180.6:c.2173-23576C>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.2173-23576C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.728 in 152,158 control chromosomes in the GnomAD database, including 40,991 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 0.73 (40991 hom., cov: 33)
• Consequence: NTRK2 NM_006180.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.866
• 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.809 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.2173-23576C>T		intron	N/A	NP_006171.2
	NTRK2	NM_001018064.3		c.2125-23576C>T		intron	N/A	NP_001018074.1	Q548C2
	NTRK2	NM_001369532.1		c.2125-23576C>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.2173-23576C>T		intron	N/A	ENSP00000277120.3	Q16620-4
	NTRK2	ENST00000323115.11	TSL:1	c.2089-23576C>T		intron	N/A	ENSP00000314586.5	A0A8J8YUT9
	NTRK2	ENST00000686324.1		c.2173-23576C>T		intron	N/A	ENSP00000510134.1	Q16620-4

Frequencies

GnomAD3 genomes AF: 0.728 AC: 110705 AN: 152040 Hom.: 40954 Cov.: 33

Gnomad AFR AF: 0.816

Gnomad AMI AF: 0.760

Gnomad AMR AF: 0.744

Gnomad ASJ AF: 0.744

Gnomad EAS AF: 0.381

Gnomad SAS AF: 0.702

Gnomad FIN AF: 0.587

Gnomad MID AF: 0.804

Gnomad NFE AF: 0.719

Gnomad OTH AF: 0.739

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

GnomAD4 genome AF: 0.728 AC: 110800 AN: 152158 Hom.: 40991 Cov.: 33 AF XY: 0.718 AC XY: 53427 AN XY: 74378

African (AFR) AF: 0.816 AC: 33878 AN: 41516

American (AMR) AF: 0.745 AC: 11384 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.744 AC: 2578 AN: 3464

East Asian (EAS) AF: 0.381 AC: 1968 AN: 5172

South Asian (SAS) AF: 0.703 AC: 3385 AN: 4818

European-Finnish (FIN) AF: 0.587 AC: 6212 AN: 10578

Middle Eastern (MID) AF: 0.796 AC: 234 AN: 294

European-Non Finnish (NFE) AF: 0.719 AC: 48908 AN: 68002

Other (OTH) AF: 0.739 AC: 1560 AN: 2112

Alfa AF: 0.729 Hom.: 5244

Bravo AF: 0.739

Asia WGS AF: 0.629 AC: 2187 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.32
DANN	Benign	0.27
PhyloP100		-0.87
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs4242630;

hg19: chr9-87611545;