rs3813296

Variant names:

• chr4-157360371-T-G
• rs3813296
• NM_001083619.3:c.2291+228T>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 6 publications found

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]

GRIA2 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with language impairment and behavioral abnormalities

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, ClinGen, Illumina, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001083619.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIA2	NM_001083619.3	MANE Select	c.2291+228T>G		intron	N/A	NP_001077088.2	P42262-1
	GRIA2	NM_000826.6		c.2291+228T>G		intron	N/A	NP_000817.5	P42262-2
	GRIA2	NM_001083620.3		c.2150+228T>G		intron	N/A	NP_001077089.2	P42262-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIA2	ENST00000264426.14	TSL:1 MANE Select	c.2291+228T>G		intron	N/A	ENSP00000264426.9	P42262-1
	GRIA2	ENST00000296526.12	TSL:1	c.2291+228T>G		intron	N/A	ENSP00000296526.7	P42262-2
	GRIA2	ENST00000393815.6	TSL:1	c.2150+228T>G		intron	N/A	ENSP00000377403.2	P42262-4

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

African (AFR) AF: 0.722 AC: 29916 AN: 41436

American (AMR) AF: 0.339 AC: 5179 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.325 AC: 1127 AN: 3470

East Asian (EAS) AF: 0.308 AC: 1581 AN: 5138

South Asian (SAS) AF: 0.177 AC: 852 AN: 4822

European-Finnish (FIN) AF: 0.297 AC: 3143 AN: 10584

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.323 AC: 21969 AN: 67974

Other (OTH) AF: 0.413 AC: 871 AN: 2110

Alfa AF: 0.392 Hom.: 1781

Bravo AF: 0.449

Asia WGS AF: 0.289 AC: 1000 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	10
DANN	Benign	0.75
PhyloP100		0.60
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3813296; hg19: chr4-158281523;