6-101682535-ATTT-ATTTT

Variant names:

• chr6-101682535-A-AT
• rs2243352
• NM_021956.5:c.724-7dupT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_021956.5(GRIK2):​c.724-7dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0358 in 849,588 control chromosomes in the GnomAD database, including 721 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.053 (651 hom., cov: 31)
  • Exomes 𝑓: 0.032 (70 hom.)
• Consequence: GRIK2 NM_021956.5 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.566
• Publications: 0 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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.178 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.724-7dupT		splice_region intron	N/A	NP_068775.1	Q13002-1
	GRIK2	NM_001166247.1		c.724-7dupT		splice_region intron	N/A	NP_001159719.1	Q8IY40
	GRIK2	NM_175768.3		c.724-7dupT		splice_region 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.724-18_724-17insT		intron	N/A	ENSP00000358130.6	Q13002-1
	GRIK2	ENST00000421544.6	TSL:1	c.724-18_724-17insT		intron	N/A	ENSP00000397026.1	Q13002-1
	GRIK2	ENST00000369138.5	TSL:1	c.724-18_724-17insT		intron	N/A	ENSP00000358134.1	Q13002-5

Frequencies

GnomAD3 genomes AF: 0.0530 AC: 7873 AN: 148522 Hom.: 649 Cov.: 31

Gnomad AFR AF: 0.181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0230

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00276

Gnomad FIN AF: 0.000413

Gnomad MID AF: 0.00974

Gnomad NFE AF: 0.000824

Gnomad OTH AF: 0.0334

GnomAD2 exomes AF: 0.0462 AC: 5378 AN: 116402 AF XY: 0.0394

Gnomad AFR exome AF: 0.245

Gnomad AMR exome AF: 0.0602

Gnomad ASJ exome AF: 0.0328

Gnomad EAS exome AF: 0.0363

Gnomad FIN exome AF: 0.00571

Gnomad NFE exome AF: 0.0208

Gnomad OTH exome AF: 0.0492

GnomAD4 exome AF: 0.0322 AC: 22537 AN: 700984 Hom.: 70 Cov.: 11 AF XY: 0.0300 AC XY: 10901 AN XY: 363106

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.191 AC: 3389 AN: 17762

American (AMR) AF: 0.0356 AC: 1084 AN: 30426

Ashkenazi Jewish (ASJ) AF: 0.0246 AC: 378 AN: 15382

East Asian (EAS) AF: 0.0209 AC: 527 AN: 25216

South Asian (SAS) AF: 0.0267 AC: 1333 AN: 49832

European-Finnish (FIN) AF: 0.0111 AC: 416 AN: 37352

Middle Eastern (MID) AF: 0.0267 AC: 103 AN: 3854

European-Non Finnish (NFE) AF: 0.0288 AC: 14101 AN: 490328

Other (OTH) AF: 0.0391 AC: 1206 AN: 30832

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0531 AC: 7887 AN: 148604 Hom.: 651 Cov.: 31 AF XY: 0.0510 AC XY: 3691 AN XY: 72404

African (AFR) AF: 0.181 AC: 7405 AN: 40876

American (AMR) AF: 0.0229 AC: 340 AN: 14832

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3422

East Asian (EAS) AF: 0.00 AC: 0 AN: 5090

South Asian (SAS) AF: 0.00256 AC: 12 AN: 4696

European-Finnish (FIN) AF: 0.000413 AC: 4 AN: 9688

Middle Eastern (MID) AF: 0.0106 AC: 3 AN: 284

European-Non Finnish (NFE) AF: 0.000824 AC: 55 AN: 66758

Other (OTH) AF: 0.0331 AC: 68 AN: 2054

Alfa AF: 0.0278 Hom.: 0

Bravo AF: 0.0601

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.57
BranchPoint Hunter		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2243352; hg19: chr6-102130410;