6-101682535-ATTT-ATTTTT

Variant names:

• chr6-101682535-A-ATT
• rs2243352
• NM_021956.5:c.724-8_724-7dupTT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_021956.5(GRIK2):​c.724-8_724-7dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000603 in 904,558 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00039 (0 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: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00168 (250/148666) while in subpopulation AFR AF = 0.00553 (226/40896). AF 95% confidence interval is 0.00494. There are 1 homozygotes in GnomAd4. There are 120 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

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.724-8_724-7dupTT		splice_region intron	N/A	NP_068775.1	Q13002-1
	GRIK2	NM_001166247.1		c.724-8_724-7dupTT		splice_region intron	N/A	NP_001159719.1	Q8IY40
	GRIK2	NM_175768.3		c.724-8_724-7dupTT		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_724-17insTT		intron	N/A	ENSP00000358130.6	Q13002-1
	GRIK2	ENST00000421544.6	TSL:1	c.724-18_724-17insTT		intron	N/A	ENSP00000397026.1	Q13002-1
	GRIK2	ENST00000369138.5	TSL:1	c.724-18_724-17insTT		intron	N/A	ENSP00000358134.1	Q13002-5

Frequencies

GnomAD3 genomes AF: 0.00168 AC: 250 AN: 148582 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00554

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00142

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00147

GnomAD2 exomes AF: 0.00122 AC: 142 AN: 116402 AF XY: 0.000969

Gnomad AFR exome AF: 0.0111

Gnomad AMR exome AF: 0.00134

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000728

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000390 AC: 295 AN: 755892 Hom.: 0 Cov.: 11 AF XY: 0.000336 AC XY: 132 AN XY: 393058

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

African (AFR) AF: 0.00702 AC: 130 AN: 18508

American (AMR) AF: 0.00103 AC: 33 AN: 32024

Ashkenazi Jewish (ASJ) AF: 0.000117 AC: 2 AN: 17164

East Asian (EAS) AF: 0.000144 AC: 4 AN: 27762

South Asian (SAS) AF: 0.000163 AC: 9 AN: 55254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41096

Middle Eastern (MID) AF: 0.000247 AC: 1 AN: 4052

European-Non Finnish (NFE) AF: 0.000173 AC: 91 AN: 526274

Other (OTH) AF: 0.000741 AC: 25 AN: 33758

⚠️ 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: 0.00168 AC: 250 AN: 148666 Hom.: 1 Cov.: 31 AF XY: 0.00166 AC XY: 120 AN XY: 72448

African (AFR) AF: 0.00553 AC: 226 AN: 40896

American (AMR) AF: 0.00141 AC: 21 AN: 14842

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3424

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4696

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9696

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66778

Other (OTH) AF: 0.00146 AC: 3 AN: 2056

Alfa AF: 0.000618 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.57
BranchPoint Hunter		1.0

Splicing

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

Other links and lift over

dbSNP: rs2243352; hg19: chr6-102130410;