rs1778934

Variant names:

• chr9-84709707-G-A
• rs1778934
• NM_006180.6:c.429-930G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_006180.6(NTRK2):​c.429-930G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.502 in 151,998 control chromosomes in the GnomAD database, including 19,416 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 0.50 (19416 hom., cov: 32)
• Consequence: NTRK2 NM_006180.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.88
• 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: 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.575 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTRK2	NM_006180.6	c.429-930G>A		intron_variant	Intron 5 of 18	ENST00000277120.8	NP_006171.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTRK2	ENST00000277120.8	c.429-930G>A		intron_variant	Intron 5 of 18	1	NM_006180.6	ENSP00000277120.3

Frequencies

GnomAD3 genomes AF: 0.502 AC: 76267 AN: 151880 Hom.: 19419 Cov.: 32

Gnomad AFR AF: 0.429

Gnomad AMI AF: 0.389

Gnomad AMR AF: 0.554

Gnomad ASJ AF: 0.497

Gnomad EAS AF: 0.592

Gnomad SAS AF: 0.557

Gnomad FIN AF: 0.572

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.516

Gnomad OTH AF: 0.499

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

GnomAD4 genome AF: 0.502 AC: 76286 AN: 151998 Hom.: 19416 Cov.: 32 AF XY: 0.507 AC XY: 37657 AN XY: 74274

African (AFR) AF: 0.428 AC: 17751 AN: 41432

American (AMR) AF: 0.554 AC: 8466 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.497 AC: 1727 AN: 3472

East Asian (EAS) AF: 0.592 AC: 3060 AN: 5168

South Asian (SAS) AF: 0.558 AC: 2688 AN: 4820

European-Finnish (FIN) AF: 0.572 AC: 6024 AN: 10534

Middle Eastern (MID) AF: 0.429 AC: 126 AN: 294

European-Non Finnish (NFE) AF: 0.516 AC: 35047 AN: 67982

Other (OTH) AF: 0.493 AC: 1042 AN: 2114

Alfa AF: 0.497 Hom.: 3562

Bravo AF: 0.494

Asia WGS AF: 0.506 AC: 1762 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	19
DANN	Benign	0.81
PhyloP100		1.9
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: rs1778934; hg19: chr9-87324622;