dbSNP rs6691840: GRIK3:p.Ser310Ala (chr1-36859876-A-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000831.4(GRIK3):c.928T>G(p.Ser310Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.274 in 1,613,172 control chromosomes in the GnomAD database, including 65,928 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.34 ( 10444 hom., cov: 32)

Exomes 𝑓: 0.27 ( 55484 hom. )

Consequence

GRIK3
NM_000831.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.959

Variant links:

Genes affected

GRIK3 (HGNC:4581): (glutamate ionotropic receptor kainate type subunit 3) 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. It is not certain if the subunit encoded by this gene is subject to RNA editing as the other 2 family members (GRIK1 and GRIK2). A Ser310Ala polymorphism has been associated with schizophrenia, and there are conflicting reports of its association with the pathogenesis of delirium tremens in alcoholics. [provided by RefSeq, Jul 2008]

GRIK3 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.8945822E-5).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.553 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIK3	NM_000831.4 link	c.928T>G	p.Ser310Ala	missense_variant	Exon 6 of 16	ENST00000373091.8	NP_000822.2	Q13003-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIK3	ENST00000373091.8 link	c.928T>G	p.Ser310Ala	missense_variant	Exon 6 of 16	1	NM_000831.4	ENSP00000362183.3		Q13003-1
GRIK3	ENST00000373093.4 link	c.928T>G	p.Ser310Ala	missense_variant	Exon 6 of 15	1		ENSP00000362185.4		Q13003-2

Frequencies

GnomAD3 genomes

AF:

0.343

AC:

52124

AN:

151968

Hom.:

10407

Cov.:

show subpopulations

Gnomad AFR

AF:

0.559

Gnomad AMI

AF:

0.234

Gnomad AMR

AF:

0.283

Gnomad ASJ

AF:

0.333

Gnomad EAS

AF:

0.0497

Gnomad SAS

AF:

0.218

Gnomad FIN

AF:

0.298

Gnomad MID

AF:

0.226

Gnomad NFE

AF:

0.267

Gnomad OTH

AF:

0.327

GnomAD3 exomes

AF:

0.268

AC:

67378

AN:

251074

Hom.:

10495

AF XY:

0.263

AC XY:

35745

AN XY:

135768

show subpopulations

Gnomad AFR exome

AF:

0.565

Gnomad AMR exome

AF:

0.252

Gnomad ASJ exome

AF:

0.348

Gnomad EAS exome

AF:

0.0444

Gnomad SAS exome

AF:

0.216

Gnomad FIN exome

AF:

0.302

Gnomad NFE exome

AF:

0.267

Gnomad OTH exome

AF:

0.285

GnomAD4 exome

AF:

0.266

AC:

389359

AN:

1461086

Hom.:

55484

Cov.:

AF XY:

0.265

AC XY:

192682

AN XY:

726882

show subpopulations

Gnomad4 AFR exome

AF:

0.573

Gnomad4 AMR exome

AF:

0.257

Gnomad4 ASJ exome

AF:

0.348

Gnomad4 EAS exome

AF:

0.0268

Gnomad4 SAS exome

AF:

0.222

Gnomad4 FIN exome

AF:

0.295

Gnomad4 NFE exome

AF:

0.266

Gnomad4 OTH exome

AF:

0.275

GnomAD4 genome

AF:

0.343

AC:

52220

AN:

152086

Hom.:

10444

Cov.:

AF XY:

0.338

AC XY:

25127

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.559

Gnomad4 AMR

AF:

0.282

Gnomad4 ASJ

AF:

0.333

Gnomad4 EAS

AF:

0.0496

Gnomad4 SAS

AF:

0.219

Gnomad4 FIN

AF:

0.298

Gnomad4 NFE

AF:

0.267

Gnomad4 OTH

AF:

0.325

Alfa

AF:

0.288

Hom.:

5929

Bravo

AF:

0.355

TwinsUK

AF:

0.260

AC:

965

ALSPAC

AF:

0.254

AC:

980

ESP6500AA

AF:

0.538

AC:

2371

ESP6500EA

AF:

0.267

AC:

2295

ExAC

AF:

0.272

AC:

32979

EpiCase

AF:

0.273

EpiControl

AF:

0.273

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.79

CADD

Benign

DANN

Benign

0.67

DEOGEN2

Benign

0.089

T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.24

T;T

MetaRNN

Benign

0.000029

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-1.5

N;N

PrimateAI

Benign

0.41

PROVEAN

Benign

0.44

N;N

REVEL

Benign

0.023

Sift

Benign

0.54

T;T

Sift4G

Benign

0.79

T;T

Polyphen

0.0

B;.

Vest4

0.057

MPC

0.54

ClinPred

0.0011

GERP RS

3.9

Varity_R

0.048

gMVP

0.32

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over