9-84673278-G-T

Variant names:

• chr9-84673278-G-T
• rs1439050
• NM_006180.6:c.212+2318G>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.212+2318G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.385 in 151,946 control chromosomes in the GnomAD database, including 12,013 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 0.38 (12013 hom., cov: 32)
• Consequence: NTRK2 NM_006180.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.128
• Publications: 15 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.521 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.212+2318G>T		intron	N/A	NP_006171.2
	NTRK2	NM_001018064.3		c.212+2318G>T		intron	N/A	NP_001018074.1
	NTRK2	NM_001369532.1		c.212+2318G>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.212+2318G>T		intron	N/A	ENSP00000277120.3
	NTRK2	ENST00000323115.11	TSL:1	c.212+2318G>T		intron	N/A	ENSP00000314586.5
	NTRK2	ENST00000304053.11	TSL:1	c.212+2318G>T		intron	N/A	ENSP00000306167.7

Frequencies

GnomAD3 genomes AF: 0.385 AC: 58381 AN: 151828 Hom.: 11976 Cov.: 32

Gnomad AFR AF: 0.526

Gnomad AMI AF: 0.482

Gnomad AMR AF: 0.364

Gnomad ASJ AF: 0.335

Gnomad EAS AF: 0.414

Gnomad SAS AF: 0.386

Gnomad FIN AF: 0.243

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.323

Gnomad OTH AF: 0.405

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

GnomAD4 genome AF: 0.385 AC: 58472 AN: 151946 Hom.: 12013 Cov.: 32 AF XY: 0.383 AC XY: 28441 AN XY: 74276

African (AFR) AF: 0.527 AC: 21828 AN: 41426

American (AMR) AF: 0.364 AC: 5558 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.335 AC: 1161 AN: 3466

East Asian (EAS) AF: 0.414 AC: 2140 AN: 5168

South Asian (SAS) AF: 0.386 AC: 1856 AN: 4814

European-Finnish (FIN) AF: 0.243 AC: 2556 AN: 10524

Middle Eastern (MID) AF: 0.483 AC: 142 AN: 294

European-Non Finnish (NFE) AF: 0.323 AC: 21926 AN: 67956

Other (OTH) AF: 0.411 AC: 867 AN: 2110

Alfa AF: 0.345 Hom.: 17236

Bravo AF: 0.402

Asia WGS AF: 0.462 AC: 1607 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.0
DANN	Benign	0.47
PhyloP100		0.13
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: rs1439050; hg19: chr9-87288193;