rs2235076

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

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

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 4.48

Publications

30 publications found

Variant links:

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

GRIK2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIK2	NM_021956.5 link	c.2601G>A	p.Met867Ile	missense_variant	Exon 17 of 17	ENST00000369134.9	NP_068775.1	Q13002-1Q8IY40A0A8D9PH75A8K0H7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIK2	ENST00000369134.9 link	c.2601G>A	p.Met867Ile	missense_variant	Exon 17 of 17	5	NM_021956.5	ENSP00000358130.6		Q13002-1F8WEZ8

Frequencies

GnomAD3 genomes

AF:

0.0174

AC:

2639

AN:

151852

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0226

AC XY:

16393

AN XY:

726118

show subpopulations

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:

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

1453

2906

4358

5811

7264

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1044

2088

3132

4176

5220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0174

AC:

2640

AN:

151970

Hom.:

Cov.:

AF XY:

0.0169

AC XY:

1259

AN XY:

74294

show subpopulations

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:

AN:

3466

East Asian (EAS)

AF:

0.000774

AC:

AN:

5168

South Asian (SAS)

AF:

0.00414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0157

AC:

166

AN:

10604

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0264

AC:

1789

AN:

67882

Other (OTH)

AF:

0.0247

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

125

250

375

500

625

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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:

ESP6500EA

AF:

0.0271

AC:

233

ExAC

AF:

0.0169

AC:

2050

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.0267

EpiControl

AF:

0.0278

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.058

T;T

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.091

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.70

T;T

MetaRNN

Benign

0.0063

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.28

N;.

PhyloP100

4.5

PrimateAI

Uncertain

0.73

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

GERP RS

4.8

Varity_R

0.26

gMVP

0.39

Mutation Taster

=94/6

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over