6-102018522-C-T

Variant names:

• chr6-102018522-C-T
• rs1335022
• NM_021956.5:c.2086-16819C>T

Variant summary

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

The NM_021956.5(GRIK2):​c.2086-16819C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.271 in 151,874 control chromosomes in the GnomAD database, including 5,987 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as association (no stars).

• Frequency: Genomes: 𝑓 0.27 (5987 hom., cov: 32)
• Consequence: GRIK2 NM_021956.5 intron
• Clinical Significance: association no assertion criteria provided O:1
• Conservation: PhyloP100: -0.0480
• Publications: 2 publications found

Genes affected

GRIK2 (HGNC:4580): (glutamate ionotropic receptor kainate type subunit 2) Glutamate receptors are the predominant excitatory neurotransmitter receptors in the mammalian brain and are activated in a variety of normal neurophysiologic processes. This gene product belongs to the kainate family of glutamate receptors, which are composed of four subunits and function as ligand-activated ion channels. The subunit encoded by this gene is subject to RNA editing at multiple sites within the first and second transmembrane domains, which is thought to alter the structure and function of the receptor complex. Alternatively spliced transcript variants encoding different isoforms have also been described for this gene. Mutations in this gene have been associated with autosomal recessive cognitive disability. [provided by RefSeq, Jul 2008]

GRIK2 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AR, AD Classification: DEFINITIVE, MODERATE Submitted by: ClinGen
• intellectual disability, autosomal recessive 6

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• neurodevelopmental disorder with impaired language and ataxia and with or without seizures

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR 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=-0.99).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.325 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIK2	NM_021956.5	c.2086-16819C>T		intron_variant	Intron 14 of 16	ENST00000369134.9	NP_068775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIK2	ENST00000369134.9	c.2086-16819C>T		intron_variant	Intron 14 of 16	5	NM_021956.5	ENSP00000358130.6

Frequencies

GnomAD3 genomes AF: 0.272 AC: 41217 AN: 151756 Hom.: 5986 Cov.: 32

Gnomad AFR AF: 0.167

Gnomad AMI AF: 0.322

Gnomad AMR AF: 0.289

Gnomad ASJ AF: 0.287

Gnomad EAS AF: 0.338

Gnomad SAS AF: 0.266

Gnomad FIN AF: 0.337

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.315

Gnomad OTH AF: 0.270

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

GnomAD4 genome AF: 0.271 AC: 41227 AN: 151874 Hom.: 5987 Cov.: 32 AF XY: 0.274 AC XY: 20301 AN XY: 74208

African (AFR) AF: 0.167 AC: 6914 AN: 41420

American (AMR) AF: 0.289 AC: 4406 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.287 AC: 996 AN: 3470

East Asian (EAS) AF: 0.338 AC: 1735 AN: 5130

South Asian (SAS) AF: 0.265 AC: 1274 AN: 4804

European-Finnish (FIN) AF: 0.337 AC: 3561 AN: 10570

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.315 AC: 21403 AN: 67912

Other (OTH) AF: 0.268 AC: 566 AN: 2112

Alfa AF: 0.299 Hom.: 3892

Bravo AF: 0.268

Asia WGS AF: 0.282 AC: 980 AN: 3478

ClinVar

Significance: association

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Lip and oral cavity carcinoma Other:1

Nov 02, 2015

Department of Biological Science, Sunandan Divatia School of Science, NMIMS University

Significance: association

Review Status: no assertion criteria provided

Collection Method: case-control

The frequency of the homozygous SNP genotype was higher in the oral cancer patients in comparison to controls, implying the role of this genotype in predisposition of oral cancer while the heterozygous genotype had a higher frequency in the controls indicating decreased risk to oral cancer. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.89
DANN	Benign	0.14
PhyloP100		-0.048
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: rs1335022; hg19: chr6-102466397; COSMIC: COSV59767090;