rs2378672

Variant names:

• chr9-85016119-C-T
• rs2378672
• NM_006180.6:c.2173-4087C>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.2173-4087C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.933 in 152,220 control chromosomes in the GnomAD database, including 66,402 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 0.93 (66402 hom., cov: 31)
• Consequence: NTRK2 NM_006180.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.221
• Publications: 8 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: Labcorp Genetics (formerly Invitae), G2P
• 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=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.976 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.2173-4087C>T		intron	N/A	NP_006171.2
	NTRK2	NM_001018064.3		c.2125-4087C>T		intron	N/A	NP_001018074.1	Q548C2
	NTRK2	NM_001369532.1		c.2125-4087C>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.2173-4087C>T		intron	N/A	ENSP00000277120.3	Q16620-4
	NTRK2	ENST00000323115.11	TSL:1	c.2089-4087C>T		intron	N/A	ENSP00000314586.5	A0A8J8YUT9
	NTRK2	ENST00000686324.1		c.2173-4087C>T		intron	N/A	ENSP00000510134.1	Q16620-4

Frequencies

GnomAD3 genomes AF: 0.933 AC: 141920 AN: 152102 Hom.: 66343 Cov.: 31

Gnomad AFR AF: 0.984

Gnomad AMI AF: 0.955

Gnomad AMR AF: 0.960

Gnomad ASJ AF: 0.911

Gnomad EAS AF: 0.880

Gnomad SAS AF: 0.858

Gnomad FIN AF: 0.848

Gnomad MID AF: 0.956

Gnomad NFE AF: 0.919

Gnomad OTH AF: 0.938

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

GnomAD4 genome AF: 0.933 AC: 142038 AN: 152220 Hom.: 66402 Cov.: 31 AF XY: 0.928 AC XY: 69060 AN XY: 74416

African (AFR) AF: 0.984 AC: 40861 AN: 41544

American (AMR) AF: 0.961 AC: 14685 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.911 AC: 3164 AN: 3472

East Asian (EAS) AF: 0.881 AC: 4544 AN: 5158

South Asian (SAS) AF: 0.857 AC: 4129 AN: 4818

European-Finnish (FIN) AF: 0.848 AC: 8984 AN: 10598

Middle Eastern (MID) AF: 0.959 AC: 282 AN: 294

European-Non Finnish (NFE) AF: 0.919 AC: 62538 AN: 68022

Other (OTH) AF: 0.937 AC: 1980 AN: 2114

Alfa AF: 0.922 Hom.: 48151

Bravo AF: 0.946

Asia WGS AF: 0.911 AC: 3168 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.0
DANN	Benign	0.66
PhyloP100		-0.22
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: rs2378672; hg19: chr9-87631034;