6-102067575-C-G

Variant names:

• chr6-102067575-C-G
• rs12198351
• NM_021956.5:c.2563-772C>G

Variant summary

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

The NM_021956.5(GRIK2):​c.2563-772C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0795 in 151,690 control chromosomes in the GnomAD database, including 625 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 0.080 (625 hom., cov: 32)
• Consequence: GRIK2 NM_021956.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.507
• Publications: 3 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=-0.86).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.107 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.2563-772C>G		intron	N/A	NP_068775.1
	GRIK2	NM_001166247.1		c.*16-772C>G		intron	N/A	NP_001159719.1
	GRIK2	NM_175768.3		c.*40-772C>G		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.2563-772C>G		intron	N/A	ENSP00000358130.6
	GRIK2	ENST00000421544.6	TSL:1	c.2563-772C>G		intron	N/A	ENSP00000397026.1
	GRIK2	ENST00000369138.5	TSL:1	c.*16-772C>G		intron	N/A	ENSP00000358134.1

Frequencies

GnomAD3 genomes AF: 0.0796 AC: 12062 AN: 151572 Hom.: 624 Cov.: 32

Gnomad AFR AF: 0.0287

Gnomad AMI AF: 0.216

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.150

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0260

Gnomad FIN AF: 0.0814

Gnomad MID AF: 0.162

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.104

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

GnomAD4 genome AF: 0.0795 AC: 12066 AN: 151690 Hom.: 625 Cov.: 32 AF XY: 0.0771 AC XY: 5712 AN XY: 74096

African (AFR) AF: 0.0287 AC: 1189 AN: 41458

American (AMR) AF: 0.111 AC: 1690 AN: 15158

Ashkenazi Jewish (ASJ) AF: 0.150 AC: 519 AN: 3460

East Asian (EAS) AF: 0.00136 AC: 7 AN: 5156

South Asian (SAS) AF: 0.0270 AC: 130 AN: 4810

European-Finnish (FIN) AF: 0.0814 AC: 861 AN: 10580

Middle Eastern (MID) AF: 0.168 AC: 49 AN: 292

European-Non Finnish (NFE) AF: 0.106 AC: 7208 AN: 67760

Other (OTH) AF: 0.103 AC: 216 AN: 2106

Alfa AF: 0.0535 Hom.: 49

Bravo AF: 0.0819

Asia WGS AF: 0.0190 AC: 66 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.49
DANN	Benign	0.52
PhyloP100		-0.51
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: rs12198351; hg19: chr6-102515450;