NM_021956.5:c.724-7delT

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_021956.5(GRIK2):​c.724-7delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0188 in 836,274 control chromosomes in the GnomAD database, including 7 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (4 hom., cov: 31)
  • Exomes 𝑓: 0.022 (3 hom.)
• Consequence: GRIK2 NM_021956.5 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• 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 -16 ACMG points.

• BP6: Variant 6-101682535-AT-A is Benign according to our data. Variant chr6-101682535-AT-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 211106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00515 (765/148582) while in subpopulation AFR AF = 0.0149 (611/40886). AF 95% confidence interval is 0.014. There are 4 homozygotes in GnomAd4. There are 376 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,AD gene

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

Frequencies

GnomAD3 genomes AF: 0.00514 AC: 764 AN: 148500 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.0150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00621

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00196

Gnomad SAS AF: 0.00276

Gnomad FIN AF: 0.000413

Gnomad MID AF: 0.00325

Gnomad NFE AF: 0.000255

Gnomad OTH AF: 0.00740

GnomAD2 exomes AF: 0.0289 AC: 3368 AN: 116402 AF XY: 0.0277

Gnomad AFR exome AF: 0.0347

Gnomad AMR exome AF: 0.0546

Gnomad ASJ exome AF: 0.0358

Gnomad EAS exome AF: 0.0387

Gnomad FIN exome AF: 0.00852

Gnomad NFE exome AF: 0.0221

Gnomad OTH exome AF: 0.0411

GnomAD4 exome AF: 0.0217 AC: 14943 AN: 687692 Hom.: 3 Cov.: 11 AF XY: 0.0211 AC XY: 7533 AN XY: 356344

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

African (AFR) AF: 0.0343 AC: 602 AN: 17526

American (AMR) AF: 0.0303 AC: 895 AN: 29560

Ashkenazi Jewish (ASJ) AF: 0.0206 AC: 308 AN: 14916

East Asian (EAS) AF: 0.0233 AC: 573 AN: 24584

South Asian (SAS) AF: 0.0250 AC: 1217 AN: 48650

European-Finnish (FIN) AF: 0.0117 AC: 421 AN: 36102

Middle Eastern (MID) AF: 0.0137 AC: 52 AN: 3792

European-Non Finnish (NFE) AF: 0.0211 AC: 10193 AN: 482248

Other (OTH) AF: 0.0225 AC: 682 AN: 30314

⚠️ 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: 0.00515 AC: 765 AN: 148582 Hom.: 4 Cov.: 31 AF XY: 0.00519 AC XY: 376 AN XY: 72408

African (AFR) AF: 0.0149 AC: 611 AN: 40886

American (AMR) AF: 0.00621 AC: 92 AN: 14826

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

East Asian (EAS) AF: 0.00216 AC: 11 AN: 5088

South Asian (SAS) AF: 0.00298 AC: 14 AN: 4694

European-Finnish (FIN) AF: 0.000413 AC: 4 AN: 9674

Middle Eastern (MID) AF: 0.00352 AC: 1 AN: 284

European-Non Finnish (NFE) AF: 0.000255 AC: 17 AN: 66754

Other (OTH) AF: 0.00732 AC: 15 AN: 2048

Alfa AF: 0.0334 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

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

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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; COSMIC: COSV59710173;