6-102068385-G-A

Variant names:

• chr6-102068385-G-A
• rs2235076
• NM_021956.5:c.2601G>A

Variant summary

Our verdict is Benign. The variant received -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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• 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
• Publications: 30 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 -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 VariationId is 129176.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 32 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIK2	NM_021956.5	MANE Select	c.2601G>A	p.Met867Ile	missense	Exon 17 of 17	NP_068775.1
	GRIK2	NM_001166247.1		c.*54G>A		3_prime_UTR	Exon 17 of 17	NP_001159719.1
	GRIK2	NM_175768.3		c.*78G>A		3_prime_UTR	Exon 17 of 17	NP_786944.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIK2	ENST00000369134.9	TSL:5 MANE Select	c.2601G>A	p.Met867Ile	missense	Exon 17 of 17	ENSP00000358130.6
	GRIK2	ENST00000421544.6	TSL:1	c.2601G>A	p.Met867Ile	missense	Exon 19 of 19	ENSP00000397026.1
	GRIK2	ENST00000369138.5	TSL:1	c.*54G>A		3_prime_UTR	Exon 17 of 17	ENSP00000358134.1

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

GnomAD2 exomes AF: 0.0175 AC: 4391 AN: 250670 AF XY: 0.0181

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 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

African (AFR) AF: 0.00423 AC: 141 AN: 33350

American (AMR) AF: 0.0130 AC: 579 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.0306 AC: 797 AN: 26040

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39676

South Asian (SAS) AF: 0.00658 AC: 567 AN: 86206

European-Finnish (FIN) AF: 0.0188 AC: 1005 AN: 53394

Middle Eastern (MID) AF: 0.0320 AC: 184 AN: 5746

European-Non Finnish (NFE) AF: 0.0258 AC: 28690 AN: 1110266

Other (OTH) AF: 0.0212 AC: 1277 AN: 60280

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

African (AFR) AF: 0.00482 AC: 200 AN: 41516

American (AMR) AF: 0.0195 AC: 297 AN: 15200

Ashkenazi Jewish (ASJ) AF: 0.0274 AC: 95 AN: 3466

East Asian (EAS) AF: 0.000774 AC: 4 AN: 5168

South Asian (SAS) AF: 0.00414 AC: 20 AN: 4826

European-Finnish (FIN) AF: 0.0157 AC: 166 AN: 10604

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0264 AC: 1789 AN: 67882

Other (OTH) AF: 0.0247 AC: 52 AN: 2102

Alfa AF: 0.0242 Hom.: 228

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

Apr 01, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.091
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0063	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.28	N
PhyloP100		4.5
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.16
Sift	Benign	0.40	T
Sift4G	Benign	0.30	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
Mutation Taster		=94/6	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: rs2235076; hg19: chr6-102516260;