rs3213608

Positions:

chr6-102035551-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_021956.5(GRIK2):c.2296G>A(p.Val766Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00118 in 1,589,202 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0028 ( 5 hom., cov: 31)

Exomes 𝑓: 0.0010 ( 22 hom. )

Consequence

GRIK2
NM_021956.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 6.95

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:

GRIK2 (HGNC:):

GRIK2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a topological_domain Extracellular (size 162) in uniprot entity GRIK2_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_021956.5

BP4

Computational evidence support a benign effect (MetaRNN=0.00972122).

BP6

Variant 6-102035551-G-A is Benign according to our data. Variant chr6-102035551-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 445349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00279 (423/151370) while in subpopulation AMR AF= 0.024 (363/15118). AF 95% confidence interval is 0.022. There are 5 homozygotes in gnomad4. There are 234 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRIK2	NM_021956.5 linkuse as main transcript	c.2296G>A	p.Val766Ile	missense_variant	15/17	ENST00000369134.9	NP_068775.1	Q13002-1Q8IY40A0A8D9PH75A8K0H7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRIK2	ENST00000369134.9 linkuse as main transcript	c.2296G>A	p.Val766Ile	missense_variant	15/17	5	NM_021956.5	ENSP00000358130.6		Q13002-1F8WEZ8

Frequencies

GnomAD3 genomes

AF:

0.00279

AC:

422

AN:

151256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000315

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0239

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00409

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000281

Gnomad OTH

AF:

0.00385

GnomAD3 exomes

AF:

0.00342

AC:

853

AN:

249648

Hom.:

AF XY:

0.00281

AC XY:

379

AN XY:

134962

show subpopulations

Gnomad AFR exome

AF:

0.000250

Gnomad AMR exome

AF:

0.0219

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00338

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000159

Gnomad OTH exome

AF:

0.00280

GnomAD4 exome

AF:

0.00101

AC:

1446

AN:

1437832

Hom.:

Cov.:

AF XY:

0.000931

AC XY:

667

AN XY:

716476

show subpopulations

Gnomad4 AFR exome

AF:

0.000305

Gnomad4 AMR exome

AF:

0.0222

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00561

Gnomad4 SAS exome

AF:

0.0000468

Gnomad4 FIN exome

AF:

0.000113

Gnomad4 NFE exome

AF:

0.000129

Gnomad4 OTH exome

AF:

0.00126

GnomAD4 genome

AF:

0.00279

AC:

423

AN:

151370

Hom.:

Cov.:

AF XY:

0.00316

AC XY:

234

AN XY:

73938

show subpopulations

Gnomad4 AFR

AF:

0.000314

Gnomad4 AMR

AF:

0.0240

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00390

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000281

Gnomad4 OTH

AF:

0.00381

Alfa

AF:

0.000792

Hom.:

Bravo

AF:

0.00363

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00255

AC:

310

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 30, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Intellectual disability, autosomal recessive 6;C5562006:Neurodevelopmental disorder with impaired language and ataxia and with or without seizures

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 25, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.50

CADD

Uncertain

DANN

Benign

0.40

DEOGEN2

Benign

0.21

T;.;.;T;.;T

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.082

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.91

D;D;D;D;D;D

MetaRNN

Benign

0.0097

T;T;T;T;T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

-1.6

N;N;N;.;.;.

PrimateAI

Uncertain

0.71

PROVEAN

Benign

0.27

N;N;N;.;N;.

REVEL

Benign

0.14

Sift

Benign

1.0

T;T;T;.;D;.

Sift4G

Benign

1.0

T;T;T;T;T;T

Polyphen

0.0060

B;B;B;.;.;.

Vest4

0.28

MVP

0.27

MPC

0.82

ClinPred

0.029

GERP RS

5.5

Varity_R

0.20

gMVP

0.36

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

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