rs61996330

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP3BP4BS1_SupportingBS2

The NM_021956.5(GRIK2):c.890C>G(p.Ser297Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00141 in 1,612,996 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 2 hom. )

Consequence

GRIK2
NM_021956.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1B:2

Conservation

PhyloP100: 7.57

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Eigen, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.31675082).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00102 (155/151950) while in subpopulation NFE AF= 0.00185 (126/67956). AF 95% confidence interval is 0.00159. There are 0 homozygotes in gnomad4. There are 65 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIK2	NM_021956.5 link	c.890C>G	p.Ser297Trp	missense_variant	Exon 7 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.890C>G	p.Ser297Trp	missense_variant	Exon 7 of 17	5	NM_021956.5	ENSP00000358130.6		Q13002-1F8WEZ8

Frequencies

GnomAD3 genomes

AF:

0.00102

AC:

155

AN:

151832

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000315

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000986

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00185

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000824

AC:

207

AN:

251138

Hom.:

AF XY:

0.000818

AC XY:

111

AN XY:

135716

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000839

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000392

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.00134

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00145

AC:

2125

AN:

1461046

Hom.:

Cov.:

AF XY:

0.00139

AC XY:

1009

AN XY:

726860

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000872

Gnomad4 ASJ exome

AF:

0.0000766

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000441

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.00179

Gnomad4 OTH exome

AF:

0.000795

GnomAD4 genome

AF:

0.00102

AC:

155

AN:

151950

Hom.:

Cov.:

AF XY:

0.000875

AC XY:

AN XY:

74272

show subpopulations

Gnomad4 AFR

AF:

0.000314

Gnomad4 AMR

AF:

0.000984

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00185

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00119

Hom.:

Bravo

AF:

0.00104

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000733

AC:

EpiCase

AF:

0.00120

EpiControl

AF:

0.00131

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 24, 2016

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Intellectual disability

Benign:1

Jan 01, 2019

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

GRIK2-related disorder

Benign:1

Jun 21, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

T;.;.;T;T;.;T

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D;D

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.32

T;T;T;T;T;T;T

MetaSVM

Uncertain

0.36

MutationAssessor

Uncertain

2.1

M;M;M;.;.;.;.

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-3.7

D;D;D;D;.;.;.

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0010

D;D;D;D;.;.;.

Sift4G

Uncertain

0.010

D;D;D;D;D;D;D

Polyphen

1.0

D;D;D;.;.;.;.

Vest4

0.84

MVP

0.92

MPC

1.2

ClinPred

0.14

GERP RS

5.8

Varity_R

0.92

gMVP

0.86

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over