rs2235076

Positions:

• chr6-102068385-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_021956.5(GRIK2):​c.2601G>A​(p.Met867Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0223 in 1,611,558 control chromosomes in the GnomAD database, including 489 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.017 (32 hom., cov: 32)
  • Exomes 𝑓: 0.023 (457 hom.)
• Consequence: GRIK2 NM_021956.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.48

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006311685).
• BP6: Variant 6-102068385-G-A is Benign according to our data. Variant chr6-102068385-G-A is described in ClinVar as [Benign]. Clinvar id is 129176.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-102068385-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0174 (2640/151970) while in subpopulation NFE AF= 0.0264 (1789/67882). AF 95% confidence interval is 0.0253. There are 32 homozygotes in gnomad4. There are 1259 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 32 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRIK2	NM_021956.5	c.2601G>A	p.Met867Ile	missense_variant	17/17	ENST00000369134.9	NP_068775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRIK2	ENST00000369134.9	c.2601G>A	p.Met867Ile	missense_variant	17/17	5	NM_021956.5	ENSP00000358130	P4

Frequencies

GnomAD3 genomes AF: 0.0174 AC: 2639 AN: 151852 Hom.: 32 Cov.: 32

Gnomad AFR AF: 0.00483

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0196

Gnomad ASJ AF: 0.0274

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.0157

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0264

Gnomad OTH AF: 0.0250

GnomAD3 exomes AF: 0.0175 AC: 4391 AN: 250670 Hom.: 50 AF XY: 0.0181 AC XY: 2447 AN XY: 135482

Gnomad AFR exome AF: 0.00457

Gnomad AMR exome AF: 0.0122

Gnomad ASJ exome AF: 0.0299

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00654

Gnomad FIN exome AF: 0.0181

Gnomad NFE exome AF: 0.0254

Gnomad OTH exome AF: 0.0214

GnomAD4 exome AF: 0.0228 AC: 33244 AN: 1459588 Hom.: 457 Cov.: 29 AF XY: 0.0226 AC XY: 16393 AN XY: 726118

Gnomad4 AFR exome AF: 0.00423

Gnomad4 AMR exome AF: 0.0130

Gnomad4 ASJ exome AF: 0.0306

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00658

Gnomad4 FIN exome AF: 0.0188

Gnomad4 NFE exome AF: 0.0258

Gnomad4 OTH exome AF: 0.0212

GnomAD4 genome AF: 0.0174 AC: 2640 AN: 151970 Hom.: 32 Cov.: 32 AF XY: 0.0169 AC XY: 1259 AN XY: 74294

Gnomad4 AFR AF: 0.00482

Gnomad4 AMR AF: 0.0195

Gnomad4 ASJ AF: 0.0274

Gnomad4 EAS AF: 0.000774

Gnomad4 SAS AF: 0.00414

Gnomad4 FIN AF: 0.0157

Gnomad4 NFE AF: 0.0264

Gnomad4 OTH AF: 0.0247

Alfa AF: 0.0252 Hom.: 123

Bravo AF: 0.0175

TwinsUK AF: 0.0286 AC: 106

ALSPAC AF: 0.0298 AC: 115

ESP6500AA AF: 0.00613 AC: 27

ESP6500EA AF: 0.0271 AC: 233

ExAC AF: 0.0169 AC: 2050

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0267

EpiControl AF: 0.0278

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	20
DANN	Benign	0.93
DEOGEN2	Benign	0.058	T;T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.091
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.70	T;T
MetaRNN	Benign	0.0063	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.28	N;.
MutationTaster	Benign	0.94	D;D;D;D;N
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.15	N;.
REVEL	Benign	0.16
Sift	Benign	0.40	T;.
Sift4G	Benign	0.30	T;T
Polyphen		0.0	B;.
Vest4		0.17
MutPred		0.21		Loss of disorder (P = 0.0421);.;
MPC		0.27
ClinPred		0.011	T
GERP RS		4.8
Varity_R		0.26
gMVP		0.39

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

Publications

LitVar

Other links and lift over

dbSNP: rs2235076; hg19: chr6-102516260;