rs6691840

chr1-36859876-A-Cchr1-36859876-A-Gchr1-36859876-A-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP2 BP4_Strong BA1

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. 13/19 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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.34 (10444 hom., cov: 32)
  • Exomes 𝑓: 0.27 (55484 hom.)
• Consequence: GRIK3 NM_000831.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.959

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]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PP2: Missense variant where missense usually causes diseases, GRIK3
• 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/exons	MANE	UniProt
GRIK3	NM_000831.4	c.928T>G	p.Ser310Ala	missense_variant	6/16	ENST00000373091.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIK3	ENST00000373091.8	c.928T>G	p.Ser310Ala	missense_variant	6/16	1	NM_000831.4	P1
GRIK3	ENST00000373093.4	c.928T>G	p.Ser310Ala	missense_variant	6/15	1

Frequencies

GnomAD3 genomes AF: 0.343 AC: 52124 AN: 151968 Hom.: 10407 Cov.: 32

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

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.: 33 AF XY: 0.265 AC XY: 192682 AN XY: 726882

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.: 32 AF XY: 0.338 AC XY: 25127 AN XY: 74340

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	T
BayesDel_noAF	Benign	-0.79
Cadd	Benign	16
Dann	Benign	0.67
DEOGEN2	Benign	0.089	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.24	T;T
MetaRNN	Benign	0.000029	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.5	N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.41	T
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	T
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

Other links and lift over

dbSNP: rs6691840; hg19: chr1-37325477; COSMIC: COSV66140566; COSMIC: COSV66140566;