rs993315

Variant names:

• chr9-84672806-T-C
• rs993315
• NM_006180.6:c.212+1846T>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.212+1846T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.504 in 152,088 control chromosomes in the GnomAD database, including 20,491 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 (20491 hom., cov: 33)
• Consequence: NTRK2 NM_006180.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.133
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.569 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTRK2	NM_006180.6	c.212+1846T>C		intron_variant	Intron 2 of 18	ENST00000277120.8	NP_006171.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTRK2	ENST00000277120.8	c.212+1846T>C		intron_variant	Intron 2 of 18	1	NM_006180.6	ENSP00000277120.3

Frequencies

GnomAD3 genomes AF: 0.504 AC: 76647 AN: 151970 Hom.: 20488 Cov.: 33

Gnomad AFR AF: 0.312

Gnomad AMI AF: 0.436

Gnomad AMR AF: 0.569

Gnomad ASJ AF: 0.562

Gnomad EAS AF: 0.586

Gnomad SAS AF: 0.576

Gnomad FIN AF: 0.635

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.573

Gnomad OTH AF: 0.509

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

GnomAD4 genome AF: 0.504 AC: 76664 AN: 152088 Hom.: 20491 Cov.: 33 AF XY: 0.509 AC XY: 37816 AN XY: 74350

African (AFR) AF: 0.312 AC: 12935 AN: 41492

American (AMR) AF: 0.570 AC: 8704 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.562 AC: 1951 AN: 3470

East Asian (EAS) AF: 0.586 AC: 3038 AN: 5180

South Asian (SAS) AF: 0.577 AC: 2784 AN: 4822

European-Finnish (FIN) AF: 0.635 AC: 6710 AN: 10562

Middle Eastern (MID) AF: 0.452 AC: 133 AN: 294

European-Non Finnish (NFE) AF: 0.573 AC: 38946 AN: 67970

Other (OTH) AF: 0.504 AC: 1067 AN: 2116

Alfa AF: 0.526 Hom.: 2799

Bravo AF: 0.488

Asia WGS AF: 0.502 AC: 1744 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	7.9
DANN	Benign	0.87
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: rs993315; hg19: chr9-87287721;