rs4302506

chr4-157317678-T-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_001083619.3(GRIA2):c.687T>C(p.His229=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.632 in 1,208,880 control chromosomes in the GnomAD database, including 246,102 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.62 (30113 hom., cov: 32)
  • Exomes 𝑓: 0.63 (215989 hom.)
• Consequence: GRIA2 NM_001083619.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.58

Genes affected

GRIA2 (HGNC:4572): (glutamate ionotropic receptor AMPA 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 a family of glutamate receptors that are sensitive to alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), and function as ligand-activated cation channels. These channels are assembled from 4 related subunits, GRIA1-4. The subunit encoded by this gene (GRIA2) is subject to RNA editing (CAG->CGG; Q->R) within the second transmembrane domain, which is thought to render the channel impermeable to Ca(2+). Human and animal studies suggest that pre-mRNA editing is essential for brain function, and defective GRIA2 RNA editing at the Q/R site may be relevant to amyotrophic lateral sclerosis (ALS) etiology. Alternative splicing, resulting in transcript variants encoding different isoforms, (including the flip and flop isoforms that vary in their signal transduction properties), has been noted for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 4-157317678-T-C is Benign according to our data. Variant chr4-157317678-T-C is described in ClinVar as [Benign]. Clinvar id is 1266895.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.59 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.801 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIA2	NM_001083619.3	c.687T>C	p.His229=	synonymous_variant	5/16	ENST00000264426.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIA2	ENST00000264426.14	c.687T>C	p.His229=	synonymous_variant	5/16	1	NM_001083619.3	P4

Frequencies

GnomAD3 genomes AF: 0.624 AC: 94767 AN: 151796 Hom.: 30101 Cov.: 32

Gnomad AFR AF: 0.513

Gnomad AMI AF: 0.562

Gnomad AMR AF: 0.710

Gnomad ASJ AF: 0.642

Gnomad EAS AF: 0.821

Gnomad SAS AF: 0.724

Gnomad FIN AF: 0.647

Gnomad MID AF: 0.598

Gnomad NFE AF: 0.647

Gnomad OTH AF: 0.623

GnomAD3 exomes AF: 0.674 AC: 161742 AN: 240144 Hom.: 55418 AF XY: 0.671 AC XY: 87557 AN XY: 130438

Gnomad AFR exome AF: 0.500

Gnomad AMR exome AF: 0.793

Gnomad ASJ exome AF: 0.650

Gnomad EAS exome AF: 0.812

Gnomad SAS exome AF: 0.722

Gnomad FIN exome AF: 0.642

Gnomad NFE exome AF: 0.637

Gnomad OTH exome AF: 0.646

GnomAD4 exome AF: 0.633 AC: 669281 AN: 1056966 Hom.: 215989 Cov.: 14 AF XY: 0.637 AC XY: 345672 AN XY: 542972

Gnomad4 AFR exome AF: 0.487

Gnomad4 AMR exome AF: 0.782

Gnomad4 ASJ exome AF: 0.640

Gnomad4 EAS exome AF: 0.839

Gnomad4 SAS exome AF: 0.712

Gnomad4 FIN exome AF: 0.640

Gnomad4 NFE exome AF: 0.612

Gnomad4 OTH exome AF: 0.630

GnomAD4 genome AF: 0.624 AC: 94811 AN: 151914 Hom.: 30113 Cov.: 32 AF XY: 0.627 AC XY: 46563 AN XY: 74222

Gnomad4 AFR AF: 0.513

Gnomad4 AMR AF: 0.711

Gnomad4 ASJ AF: 0.642

Gnomad4 EAS AF: 0.822

Gnomad4 SAS AF: 0.722

Gnomad4 FIN AF: 0.647

Gnomad4 NFE AF: 0.647

Gnomad4 OTH AF: 0.624

Alfa AF: 0.628 Hom.: 13748

Bravo AF: 0.622

Asia WGS AF: 0.730 AC: 2530 AN: 3464

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 11, 2020

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
Cadd	Benign	9.3
Dann	Benign	0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs4302506; hg19: chr4-158238830; COSMIC: COSV52388677; COSMIC: COSV52388677;