rs4691396

Variant names:

• chr4-157384959-T-C
• rs4691396
• ENST00000703754.1:n.*121-1155T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000703754.1(GRIA2):​n.*121-1155T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.427 in 152,122 control chromosomes in the GnomAD database, including 16,492 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 (16492 hom., cov: 32)
• Consequence: GRIA2 ENST00000703754.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.44
• Publications: 1 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: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, G2P, Illumina

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• 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 rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIA2	ENST00000703754.1	n.*121-1155T>C		intron_variant	Intron 16 of 16			ENSP00000515463.1

Frequencies

GnomAD3 genomes AF: 0.427 AC: 64965 AN: 152004 Hom.: 16480 Cov.: 32

Gnomad AFR AF: 0.722

Gnomad AMI AF: 0.342

Gnomad AMR AF: 0.339

Gnomad ASJ AF: 0.315

Gnomad EAS AF: 0.307

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.297

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.323

Gnomad OTH AF: 0.411

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

GnomAD4 genome AF: 0.427 AC: 65015 AN: 152122 Hom.: 16492 Cov.: 32 AF XY: 0.420 AC XY: 31262 AN XY: 74362

African (AFR) AF: 0.721 AC: 29961 AN: 41528

American (AMR) AF: 0.339 AC: 5179 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.315 AC: 1091 AN: 3464

East Asian (EAS) AF: 0.307 AC: 1584 AN: 5168

South Asian (SAS) AF: 0.177 AC: 855 AN: 4822

European-Finnish (FIN) AF: 0.297 AC: 3139 AN: 10566

Middle Eastern (MID) AF: 0.320 AC: 94 AN: 294

European-Non Finnish (NFE) AF: 0.323 AC: 21932 AN: 67978

Other (OTH) AF: 0.412 AC: 869 AN: 2110

Alfa AF: 0.393 Hom.: 1787

Bravo AF: 0.449

Asia WGS AF: 0.287 AC: 990 AN: 3464

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	12
DANN	Benign	0.45
PhyloP100		2.4

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4691396; hg19: chr4-158306111; COSMIC: COSV61339898;