9-84893781-G-T

Variant names:

• chr9-84893781-G-T
• rs10868236
• NM_006180.6:c.1633+26350G>T

Variant summary

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

The NM_006180.6(NTRK2):​c.1633+26350G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.862 in 152,194 control chromosomes in the GnomAD database, including 56,674 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 0.86 (56674 hom., cov: 31)
• Consequence: NTRK2 NM_006180.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.356
• 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.916 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTRK2	NM_006180.6	c.1633+26350G>T		intron_variant	Intron 14 of 18	ENST00000277120.8	NP_006171.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTRK2	ENST00000277120.8	c.1633+26350G>T		intron_variant	Intron 14 of 18	1	NM_006180.6	ENSP00000277120.3

Frequencies

GnomAD3 genomes AF: 0.862 AC: 131067 AN: 152076 Hom.: 56633 Cov.: 31

Gnomad AFR AF: 0.924

Gnomad AMI AF: 0.895

Gnomad AMR AF: 0.864

Gnomad ASJ AF: 0.818

Gnomad EAS AF: 0.741

Gnomad SAS AF: 0.920

Gnomad FIN AF: 0.809

Gnomad MID AF: 0.778

Gnomad NFE AF: 0.840

Gnomad OTH AF: 0.843

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

GnomAD4 genome AF: 0.862 AC: 131163 AN: 152194 Hom.: 56674 Cov.: 31 AF XY: 0.861 AC XY: 64085 AN XY: 74392

African (AFR) AF: 0.924 AC: 38381 AN: 41544

American (AMR) AF: 0.864 AC: 13215 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.818 AC: 2841 AN: 3472

East Asian (EAS) AF: 0.740 AC: 3825 AN: 5166

South Asian (SAS) AF: 0.920 AC: 4429 AN: 4816

European-Finnish (FIN) AF: 0.809 AC: 8563 AN: 10586

Middle Eastern (MID) AF: 0.772 AC: 227 AN: 294

European-Non Finnish (NFE) AF: 0.840 AC: 57083 AN: 67990

Other (OTH) AF: 0.844 AC: 1785 AN: 2114

Alfa AF: 0.846 Hom.: 15701

Bravo AF: 0.866

Asia WGS AF: 0.847 AC: 2945 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.53
DANN	Benign	0.49
PhyloP100		-0.36
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: rs10868236; hg19: chr9-87508696;