rs3813296

Positions:

• chr4-157360371-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001083619.3(GRIA2):​c.2291+228T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.428 in 152,012 control chromosomes in the GnomAD database, including 16,500 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.43 (16500 hom., cov: 32)
• Consequence: GRIA2 NM_001083619.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.597

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.715 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIA2	NM_001083619.3	c.2291+228T>G		intron_variant		ENST00000264426.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIA2	ENST00000264426.14	c.2291+228T>G		intron_variant		1	NM_001083619.3	P4

Frequencies

GnomAD3 genomes AF: 0.428 AC: 64973 AN: 151892 Hom.: 16488 Cov.: 32

Gnomad AFR AF: 0.723

Gnomad AMI AF: 0.322

Gnomad AMR AF: 0.340

Gnomad ASJ AF: 0.325

Gnomad EAS AF: 0.308

Gnomad SAS AF: 0.177

Gnomad FIN AF: 0.297

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.323

Gnomad OTH AF: 0.412

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.428 AC: 65024 AN: 152012 Hom.: 16500 Cov.: 32 AF XY: 0.421 AC XY: 31242 AN XY: 74294

Gnomad4 AFR AF: 0.722

Gnomad4 AMR AF: 0.339

Gnomad4 ASJ AF: 0.325

Gnomad4 EAS AF: 0.308

Gnomad4 SAS AF: 0.177

Gnomad4 FIN AF: 0.297

Gnomad4 NFE AF: 0.323

Gnomad4 OTH AF: 0.413

Alfa AF: 0.379 Hom.: 1587

Bravo AF: 0.449

Asia WGS AF: 0.289 AC: 1000 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	10
DANN	Benign	0.75

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

Other links and lift over

dbSNP: rs3813296; hg19: chr4-158281523;