rs1187329

Variant names:

• chr9-84674365-A-G
• rs1187329
• NM_006180.6:c.212+3405A>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.212+3405A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.527 in 152,060 control chromosomes in the GnomAD database, including 21,781 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 0.53 (21781 hom., cov: 33)
• Consequence: NTRK2 NM_006180.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.752
• Publications: 5 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=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.569 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+3405A>G		intron	N/A	NP_006171.2
	NTRK2	NM_001018064.3		c.212+3405A>G		intron	N/A	NP_001018074.1
	NTRK2	NM_001369532.1		c.212+3405A>G		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+3405A>G		intron	N/A	ENSP00000277120.3
	NTRK2	ENST00000323115.11	TSL:1	c.212+3405A>G		intron	N/A	ENSP00000314586.5
	NTRK2	ENST00000304053.11	TSL:1	c.212+3405A>G		intron	N/A	ENSP00000306167.7

Frequencies

GnomAD3 genomes AF: 0.528 AC: 80187 AN: 151944 Hom.: 21781 Cov.: 33

Gnomad AFR AF: 0.392

Gnomad AMI AF: 0.435

Gnomad AMR AF: 0.579

Gnomad ASJ AF: 0.563

Gnomad EAS AF: 0.587

Gnomad SAS AF: 0.576

Gnomad FIN AF: 0.635

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.574

Gnomad OTH AF: 0.526

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

GnomAD4 genome AF: 0.527 AC: 80206 AN: 152060 Hom.: 21781 Cov.: 33 AF XY: 0.532 AC XY: 39531 AN XY: 74366

African (AFR) AF: 0.392 AC: 16252 AN: 41468

American (AMR) AF: 0.579 AC: 8853 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.563 AC: 1952 AN: 3470

East Asian (EAS) AF: 0.587 AC: 3033 AN: 5170

South Asian (SAS) AF: 0.577 AC: 2785 AN: 4824

European-Finnish (FIN) AF: 0.635 AC: 6728 AN: 10588

Middle Eastern (MID) AF: 0.459 AC: 135 AN: 294

European-Non Finnish (NFE) AF: 0.574 AC: 38971 AN: 67946

Other (OTH) AF: 0.521 AC: 1101 AN: 2112

Alfa AF: 0.553 Hom.: 6289

Bravo AF: 0.515

Asia WGS AF: 0.505 AC: 1759 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.031
DANN	Benign	0.69
PhyloP100		-0.75
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: rs1187329; hg19: chr9-87289280;