9-84994469-T-C

Variant names:

• chr9-84994469-T-C
• rs4419891
• NM_006180.6:c.2173-25737T>C

Variant summary

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

The NM_006180.6(NTRK2):​c.2173-25737T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.676 in 152,096 control chromosomes in the GnomAD database, including 35,336 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 0.68 (35336 hom., cov: 32)
• Consequence: NTRK2 NM_006180.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0660
• Publications: 2 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 (NFE) allele frequency at 95% confidence interval = 0.712 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTRK2	NM_006180.6	c.2173-25737T>C		intron_variant	Intron 17 of 18	ENST00000277120.8	NP_006171.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTRK2	ENST00000277120.8	c.2173-25737T>C		intron_variant	Intron 17 of 18	1	NM_006180.6	ENSP00000277120.3

Frequencies

GnomAD3 genomes AF: 0.677 AC: 102828 AN: 151978 Hom.: 35331 Cov.: 32

Gnomad AFR AF: 0.675

Gnomad AMI AF: 0.777

Gnomad AMR AF: 0.673

Gnomad ASJ AF: 0.735

Gnomad EAS AF: 0.288

Gnomad SAS AF: 0.660

Gnomad FIN AF: 0.587

Gnomad MID AF: 0.794

Gnomad NFE AF: 0.717

Gnomad OTH AF: 0.704

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

GnomAD4 genome AF: 0.676 AC: 102875 AN: 152096 Hom.: 35336 Cov.: 32 AF XY: 0.665 AC XY: 49467 AN XY: 74364

African (AFR) AF: 0.675 AC: 27982 AN: 41472

American (AMR) AF: 0.673 AC: 10275 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.735 AC: 2549 AN: 3470

East Asian (EAS) AF: 0.288 AC: 1494 AN: 5184

South Asian (SAS) AF: 0.660 AC: 3180 AN: 4820

European-Finnish (FIN) AF: 0.587 AC: 6221 AN: 10590

Middle Eastern (MID) AF: 0.786 AC: 231 AN: 294

European-Non Finnish (NFE) AF: 0.717 AC: 48758 AN: 67970

Other (OTH) AF: 0.700 AC: 1478 AN: 2110

Alfa AF: 0.710 Hom.: 48268

Bravo AF: 0.678

Asia WGS AF: 0.539 AC: 1876 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.9
DANN	Benign	0.37
PhyloP100		0.066
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: rs4419891; hg19: chr9-87609384;