rs1036914

Variant names:

• chr9-84823244-A-G
• rs1036914
• NM_006180.6:c.1397-37796A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006180.6(NTRK2):​c.1397-37796A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.347 in 152,112 control chromosomes in the GnomAD database, including 9,740 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 0.35 (9740 hom., cov: 33)
• Consequence: NTRK2 NM_006180.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.589
• Publications: 1 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=-0.61).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.479 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.1397-37796A>G		intron	N/A	NP_006171.2
	NTRK2	NM_001018064.3		c.1397-43999A>G		intron	N/A	NP_001018074.1	Q548C2
	NTRK2	NM_001369532.1		c.1397-43999A>G		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.1397-37796A>G		intron	N/A	ENSP00000277120.3	Q16620-4
	NTRK2	ENST00000323115.11	TSL:1	c.1361-43999A>G		intron	N/A	ENSP00000314586.5	A0A8J8YUT9
	NTRK2	ENST00000304053.11	TSL:1	c.1397-43999A>G		intron	N/A	ENSP00000306167.7	Q16620-3

Frequencies

GnomAD3 genomes AF: 0.347 AC: 52728 AN: 151994 Hom.: 9725 Cov.: 33

Gnomad AFR AF: 0.485

Gnomad AMI AF: 0.219

Gnomad AMR AF: 0.320

Gnomad ASJ AF: 0.335

Gnomad EAS AF: 0.316

Gnomad SAS AF: 0.322

Gnomad FIN AF: 0.259

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.288

Gnomad OTH AF: 0.362

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

GnomAD4 genome AF: 0.347 AC: 52774 AN: 152112 Hom.: 9740 Cov.: 33 AF XY: 0.345 AC XY: 25635 AN XY: 74380

African (AFR) AF: 0.485 AC: 20111 AN: 41488

American (AMR) AF: 0.319 AC: 4881 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.335 AC: 1162 AN: 3470

East Asian (EAS) AF: 0.316 AC: 1638 AN: 5180

South Asian (SAS) AF: 0.321 AC: 1550 AN: 4824

European-Finnish (FIN) AF: 0.259 AC: 2745 AN: 10582

Middle Eastern (MID) AF: 0.344 AC: 101 AN: 294

European-Non Finnish (NFE) AF: 0.289 AC: 19610 AN: 67966

Other (OTH) AF: 0.368 AC: 777 AN: 2114

Alfa AF: 0.315 Hom.: 1043

Bravo AF: 0.359

Asia WGS AF: 0.384 AC: 1332 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	8.0
DANN	Benign	0.58
PhyloP100		-0.59
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: rs1036914;

hg19: chr9-87438159;