6-101398678-G-A

Variant names:

• chr6-101398678-G-A
• rs2852512
• NM_021956.5:c.-293-307G>A

Variant summary

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

The NM_021956.5(GRIK2):​c.-293-307G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.203 in 215,342 control chromosomes in the GnomAD database, including 5,230 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 0.21 (4120 hom., cov: 32)
  • Exomes 𝑓: 0.17 (1110 hom.)
• Consequence: GRIK2 NM_021956.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.502
• Publications: 1 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=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.326 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021956.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIK2	NM_021956.5	MANE Select	c.-293-307G>A		intron	N/A	NP_068775.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIK2	ENST00000369134.9	TSL:5 MANE Select	c.-293-307G>A		intron	N/A	ENSP00000358130.6
	GRIK2	ENST00000421544.6	TSL:1	c.-293-307G>A		intron	N/A	ENSP00000397026.1
	GRIK2	ENST00000681975.1		c.-293-307G>A		intron	N/A	ENSP00000508014.1

Frequencies

GnomAD3 genomes AF: 0.214 AC: 32575 AN: 151952 Hom.: 4108 Cov.: 32

Gnomad AFR AF: 0.330

Gnomad AMI AF: 0.148

Gnomad AMR AF: 0.122

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.0125

Gnomad SAS AF: 0.0951

Gnomad FIN AF: 0.217

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.193

Gnomad OTH AF: 0.161

GnomAD4 exome AF: 0.175 AC: 11044 AN: 63272 Hom.: 1110 AF XY: 0.172 AC XY: 5568 AN XY: 32436

African (AFR) AF: 0.325 AC: 762 AN: 2346

American (AMR) AF: 0.112 AC: 199 AN: 1784

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 363 AN: 2526

East Asian (EAS) AF: 0.0125 AC: 55 AN: 4400

South Asian (SAS) AF: 0.0807 AC: 46 AN: 570

European-Finnish (FIN) AF: 0.203 AC: 881 AN: 4348

Middle Eastern (MID) AF: 0.140 AC: 50 AN: 358

European-Non Finnish (NFE) AF: 0.186 AC: 7894 AN: 42448

Other (OTH) AF: 0.177 AC: 794 AN: 4492

GnomAD4 genome AF: 0.214 AC: 32614 AN: 152070 Hom.: 4120 Cov.: 32 AF XY: 0.211 AC XY: 15687 AN XY: 74350

African (AFR) AF: 0.330 AC: 13681 AN: 41438

American (AMR) AF: 0.122 AC: 1857 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 592 AN: 3468

East Asian (EAS) AF: 0.0127 AC: 66 AN: 5188

South Asian (SAS) AF: 0.0950 AC: 458 AN: 4820

European-Finnish (FIN) AF: 0.217 AC: 2299 AN: 10584

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.193 AC: 13152 AN: 67982

Other (OTH) AF: 0.159 AC: 336 AN: 2110

Alfa AF: 0.217 Hom.: 597

Bravo AF: 0.213

Asia WGS AF: 0.0690 AC: 242 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	9.6
DANN	Benign	0.60
PhyloP100		0.50
PromoterAI		0.033	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2852512; hg19: chr6-101846554; COSMIC: COSV59721548;