rs3213607

Variant names:

• chr6-102035481-C-A
• rs3213607
• NM_021956.5:c.2226C>A

Your query was ambiguous. Multiple possible variants found:

• chr6-102035481-C-A
• chr6-102035481-C-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_021956.5(GRIK2):​c.2226C>A​(p.Ile742Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0655 in 1,608,300 control chromosomes in the GnomAD database, including 3,612 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.068 (351 hom., cov: 31)
  • Exomes 𝑓: 0.065 (3261 hom.)
• Consequence: GRIK2 NM_021956.5 synonymous
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.309
• Publications: 19 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 6-102035481-C-A is Benign according to our data. Variant chr6-102035481-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 129172.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-0.309 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.079 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.2226C>A	p.Ile742Ile	synonymous	Exon 15 of 17	NP_068775.1
	GRIK2	NM_001166247.1		c.2226C>A	p.Ile742Ile	synonymous	Exon 14 of 17	NP_001159719.1
	GRIK2	NM_175768.3		c.2226C>A	p.Ile742Ile	synonymous	Exon 14 of 17	NP_786944.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIK2	ENST00000369134.9	TSL:5 MANE Select	c.2226C>A	p.Ile742Ile	synonymous	Exon 15 of 17	ENSP00000358130.6
	GRIK2	ENST00000421544.6	TSL:1	c.2226C>A	p.Ile742Ile	synonymous	Exon 17 of 19	ENSP00000397026.1
	GRIK2	ENST00000369138.5	TSL:1	c.2226C>A	p.Ile742Ile	synonymous	Exon 14 of 17	ENSP00000358134.1

Frequencies

GnomAD3 genomes AF: 0.0684 AC: 10328 AN: 151102 Hom.: 350 Cov.: 31

Gnomad AFR AF: 0.0813

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0602

Gnomad ASJ AF: 0.0480

Gnomad EAS AF: 0.0541

Gnomad SAS AF: 0.0554

Gnomad FIN AF: 0.0767

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0651

Gnomad OTH AF: 0.0646

GnomAD2 exomes AF: 0.0649 AC: 16261 AN: 250652 AF XY: 0.0642

Gnomad AFR exome AF: 0.0823

Gnomad AMR exome AF: 0.0760

Gnomad ASJ exome AF: 0.0385

Gnomad EAS exome AF: 0.0499

Gnomad FIN exome AF: 0.0717

Gnomad NFE exome AF: 0.0644

Gnomad OTH exome AF: 0.0616

GnomAD4 exome AF: 0.0652 AC: 95072 AN: 1457080 Hom.: 3261 Cov.: 29 AF XY: 0.0650 AC XY: 47097 AN XY: 725072

African (AFR) AF: 0.0797 AC: 2647 AN: 33216

American (AMR) AF: 0.0740 AC: 3297 AN: 44572

Ashkenazi Jewish (ASJ) AF: 0.0414 AC: 1076 AN: 25988

East Asian (EAS) AF: 0.0649 AC: 2572 AN: 39642

South Asian (SAS) AF: 0.0576 AC: 4959 AN: 86098

European-Finnish (FIN) AF: 0.0744 AC: 3974 AN: 53390

Middle Eastern (MID) AF: 0.0298 AC: 171 AN: 5738

European-Non Finnish (NFE) AF: 0.0656 AC: 72715 AN: 1108302

Other (OTH) AF: 0.0609 AC: 3661 AN: 60134

GnomAD4 genome AF: 0.0683 AC: 10334 AN: 151220 Hom.: 351 Cov.: 31 AF XY: 0.0685 AC XY: 5060 AN XY: 73852

African (AFR) AF: 0.0813 AC: 3363 AN: 41354

American (AMR) AF: 0.0598 AC: 903 AN: 15094

Ashkenazi Jewish (ASJ) AF: 0.0480 AC: 165 AN: 3436

East Asian (EAS) AF: 0.0540 AC: 275 AN: 5094

South Asian (SAS) AF: 0.0552 AC: 266 AN: 4816

European-Finnish (FIN) AF: 0.0767 AC: 812 AN: 10582

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0651 AC: 4396 AN: 67542

Other (OTH) AF: 0.0668 AC: 140 AN: 2096

Alfa AF: 0.0622 Hom.: 554

Bravo AF: 0.0662

Asia WGS AF: 0.0710 AC: 246 AN: 3478

EpiCase AF: 0.0590

EpiControl AF: 0.0614

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	2.4
DANN	Benign	0.68
PhyloP100		-0.31
Mutation Taster		=97/3	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: rs3213607; hg19: chr6-102483356; COSMIC: COSV59740169;