6-101686147-C-G

Variant names:

• chr6-101686147-C-G
• rs2786251
• NM_021956.5:c.778-33C>G

Variant summary

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

The NM_021956.5(GRIK2):​c.778-33C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.275 in 1,574,708 control chromosomes in the GnomAD database, including 69,367 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 0.38 (13502 hom., cov: 32)
  • Exomes 𝑓: 0.26 (55865 hom.)
• Consequence: GRIK2 NM_021956.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.644
• Publications: 5 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: AD, AR Classification: DEFINITIVE, MODERATE Submitted by: ClinGen
• intellectual disability, autosomal recessive 6

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

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• 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=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.645 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIK2	NM_021956.5	MANE Select	c.778-33C>G		intron	N/A	NP_068775.1	Q13002-1
	GRIK2	NM_001166247.1		c.778-33C>G		intron	N/A	NP_001159719.1	Q8IY40
	GRIK2	NM_175768.3		c.778-33C>G		intron	N/A	NP_786944.1	Q8IY40

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIK2	ENST00000369134.9	TSL:5 MANE Select	c.778-33C>G		intron	N/A	ENSP00000358130.6	Q13002-1
	GRIK2	ENST00000421544.6	TSL:1	c.778-33C>G		intron	N/A	ENSP00000397026.1	Q13002-1
	GRIK2	ENST00000369138.5	TSL:1	c.778-33C>G		intron	N/A	ENSP00000358134.1	Q13002-5

Frequencies

GnomAD3 genomes AF: 0.380 AC: 57647 AN: 151756 Hom.: 13473 Cov.: 32

Gnomad AFR AF: 0.651

Gnomad AMI AF: 0.190

Gnomad AMR AF: 0.372

Gnomad ASJ AF: 0.295

Gnomad EAS AF: 0.510

Gnomad SAS AF: 0.386

Gnomad FIN AF: 0.273

Gnomad MID AF: 0.334

Gnomad NFE AF: 0.231

Gnomad OTH AF: 0.345

GnomAD2 exomes AF: 0.330 AC: 79437 AN: 241012 AF XY: 0.320

Gnomad AFR exome AF: 0.659

Gnomad AMR exome AF: 0.417

Gnomad ASJ exome AF: 0.302

Gnomad EAS exome AF: 0.493

Gnomad FIN exome AF: 0.268

Gnomad NFE exome AF: 0.232

Gnomad OTH exome AF: 0.292

GnomAD4 exome AF: 0.264 AC: 375342 AN: 1422836 Hom.: 55865 Cov.: 24 AF XY: 0.266 AC XY: 188285 AN XY: 707580

African (AFR) AF: 0.657 AC: 21311 AN: 32424

American (AMR) AF: 0.408 AC: 17473 AN: 42850

Ashkenazi Jewish (ASJ) AF: 0.307 AC: 7681 AN: 25004

East Asian (EAS) AF: 0.518 AC: 20316 AN: 39252

South Asian (SAS) AF: 0.374 AC: 31294 AN: 83720

European-Finnish (FIN) AF: 0.267 AC: 14053 AN: 52710

Middle Eastern (MID) AF: 0.352 AC: 1961 AN: 5576

European-Non Finnish (NFE) AF: 0.226 AC: 244226 AN: 1082494

Other (OTH) AF: 0.290 AC: 17027 AN: 58806

GnomAD4 genome AF: 0.380 AC: 57732 AN: 151872 Hom.: 13502 Cov.: 32 AF XY: 0.384 AC XY: 28498 AN XY: 74214

African (AFR) AF: 0.651 AC: 26973 AN: 41430

American (AMR) AF: 0.372 AC: 5667 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.295 AC: 1021 AN: 3466

East Asian (EAS) AF: 0.509 AC: 2613 AN: 5132

South Asian (SAS) AF: 0.386 AC: 1858 AN: 4814

European-Finnish (FIN) AF: 0.273 AC: 2880 AN: 10556

Middle Eastern (MID) AF: 0.329 AC: 96 AN: 292

European-Non Finnish (NFE) AF: 0.231 AC: 15716 AN: 67926

Other (OTH) AF: 0.347 AC: 735 AN: 2116

Alfa AF: 0.315 Hom.: 1658

Bravo AF: 0.399

Asia WGS AF: 0.483 AC: 1678 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.1
DANN	Benign	0.54
PhyloP100		-0.64
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: rs2786251; hg19: chr6-102134022; COSMIC: COSV59775755;