NM_021956.5:c.1525-4174G>A

Variant names:

• chr6-101885466-G-A
• rs1417182
• NM_021956.5:c.1525-4174G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_021956.5(GRIK2):​c.1525-4174G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.397 in 151,796 control chromosomes in the GnomAD database, including 13,380 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.40 (13380 hom., cov: 31)
• Consequence: GRIK2 NM_021956.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.14
• Publications: 5 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.509 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIK2	NM_021956.5	MANE Select	c.1525-4174G>A		intron	N/A	NP_068775.1
	GRIK2	NM_001166247.1		c.1525-4174G>A		intron	N/A	NP_001159719.1
	GRIK2	NM_175768.3		c.1525-4174G>A		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.1525-4174G>A		intron	N/A	ENSP00000358130.6
	GRIK2	ENST00000421544.6	TSL:1	c.1525-4174G>A		intron	N/A	ENSP00000397026.1
	GRIK2	ENST00000369138.5	TSL:1	c.1525-4174G>A		intron	N/A	ENSP00000358134.1

Frequencies

GnomAD3 genomes AF: 0.397 AC: 60287 AN: 151678 Hom.: 13383 Cov.: 31

Gnomad AFR AF: 0.231

Gnomad AMI AF: 0.385

Gnomad AMR AF: 0.377

Gnomad ASJ AF: 0.517

Gnomad EAS AF: 0.103

Gnomad SAS AF: 0.421

Gnomad FIN AF: 0.417

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.513

Gnomad OTH AF: 0.437

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.397 AC: 60281 AN: 151796 Hom.: 13380 Cov.: 31 AF XY: 0.391 AC XY: 29015 AN XY: 74192

African (AFR) AF: 0.230 AC: 9544 AN: 41412

American (AMR) AF: 0.376 AC: 5730 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.517 AC: 1790 AN: 3462

East Asian (EAS) AF: 0.103 AC: 533 AN: 5162

South Asian (SAS) AF: 0.422 AC: 2032 AN: 4820

European-Finnish (FIN) AF: 0.417 AC: 4394 AN: 10546

Middle Eastern (MID) AF: 0.589 AC: 172 AN: 292

European-Non Finnish (NFE) AF: 0.513 AC: 34826 AN: 67850

Other (OTH) AF: 0.431 AC: 910 AN: 2112

Alfa AF: 0.478 Hom.: 32167

Bravo AF: 0.385

Asia WGS AF: 0.265 AC: 921 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.030
DANN	Benign	0.50
PhyloP100		-1.1
Mutation Taster		=100/0	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: rs1417182; hg19: chr6-102333341; COSMIC: COSV59766604;