4-157281250-G-C

Variant names:

• chr4-157281250-G-C
• rs10517665
• NM_001083619.3:c.230-22302G>C

Variant summary

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

The NM_001083619.3(GRIA2):​c.230-22302G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.196 in 151,922 control chromosomes in the GnomAD database, including 3,350 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 0.20 (3350 hom., cov: 31)
• Consequence: GRIA2 NM_001083619.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.462
• Publications: 3 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.304 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.230-22302G>C		intron	N/A	NP_001077088.2	P42262-1
	GRIA2	NM_000826.6		c.230-22302G>C		intron	N/A	NP_000817.5	P42262-2
	GRIA2	NM_001083620.3		c.89-22302G>C		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.230-22302G>C		intron	N/A	ENSP00000264426.9	P42262-1
	GRIA2	ENST00000296526.12	TSL:1	c.230-22302G>C		intron	N/A	ENSP00000296526.7	P42262-2
	GRIA2	ENST00000393815.6	TSL:1	c.89-22302G>C		intron	N/A	ENSP00000377403.2	P42262-4

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29807 AN: 151802 Hom.: 3339 Cov.: 31

Gnomad AFR AF: 0.309

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.150

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.160

Gnomad SAS AF: 0.0722

Gnomad FIN AF: 0.165

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.160

Gnomad OTH AF: 0.192

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

GnomAD4 genome AF: 0.196 AC: 29851 AN: 151922 Hom.: 3350 Cov.: 31 AF XY: 0.194 AC XY: 14373 AN XY: 74244

African (AFR) AF: 0.309 AC: 12794 AN: 41422

American (AMR) AF: 0.150 AC: 2287 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 485 AN: 3466

East Asian (EAS) AF: 0.159 AC: 816 AN: 5126

South Asian (SAS) AF: 0.0727 AC: 350 AN: 4814

European-Finnish (FIN) AF: 0.165 AC: 1747 AN: 10586

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.160 AC: 10841 AN: 67952

Other (OTH) AF: 0.194 AC: 409 AN: 2112

Alfa AF: 0.0655 Hom.: 68

Bravo AF: 0.203

Asia WGS AF: 0.142 AC: 494 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.0
DANN	Benign	0.23
PhyloP100		0.46
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: rs10517665; hg19: chr4-158202402;