rs2243352

Variant names:

• chr6-101682535-ATTT-A
• rs2243352
• NM_021956.5:c.724-9_724-7delTTT

Your query was ambiguous. Multiple possible variants found:

• chr6-101682535-ATTT-A
• chr6-101682535-ATTT-AT
• chr6-101682535-ATTT-ATT
• chr6-101682535-ATTT-ATTTT
• chr6-101682535-ATTT-ATTTTT
• chr6-101682535-ATTT-ATTTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000369134.9(GRIK2):​c.724-17_724-15delTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000396 in 756,912 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000040 (0 hom.)
• Consequence: GRIK2 ENST00000369134.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.600
• 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: 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000369134.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIK2	NM_021956.5	MANE Select	c.724-9_724-7delTTT		splice_region intron	N/A	NP_068775.1
	GRIK2	NM_001166247.1		c.724-9_724-7delTTT		splice_region intron	N/A	NP_001159719.1
	GRIK2	NM_175768.3		c.724-9_724-7delTTT		splice_region intron	N/A	NP_786944.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIK2	ENST00000369134.9	TSL:5 MANE Select	c.724-17_724-15delTTT		intron	N/A	ENSP00000358130.6
	GRIK2	ENST00000421544.6	TSL:1	c.724-17_724-15delTTT		intron	N/A	ENSP00000397026.1
	GRIK2	ENST00000369138.5	TSL:1	c.724-17_724-15delTTT		intron	N/A	ENSP00000358134.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000396 AC: 3 AN: 756912 Hom.: 0 AF XY: 0.00000508 AC XY: 2 AN XY: 393566

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

African (AFR) AF: 0.00 AC: 0 AN: 18594

American (AMR) AF: 0.00 AC: 0 AN: 32072

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17182

East Asian (EAS) AF: 0.00 AC: 0 AN: 27812

South Asian (SAS) AF: 0.0000181 AC: 1 AN: 55360

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41116

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4054

European-Non Finnish (NFE) AF: 0.00000380 AC: 2 AN: 526918

Other (OTH) AF: 0.00 AC: 0 AN: 33804

⚠️ 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 Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.60
BranchPoint Hunter		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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;