rs11946396

Variant names:

• chr4-157240151-A-G
• rs11946396
• NM_001083619.3:c.229+18344A>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.229+18344A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.409 in 151,932 control chromosomes in the GnomAD database, including 14,802 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 0.41 (14802 hom., cov: 32)
• Consequence: GRIA2 NM_001083619.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.00
• Publications: 2 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.664 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIA2	NM_001083619.3	c.229+18344A>G		intron_variant	Intron 2 of 15	ENST00000264426.14	NP_001077088.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIA2	ENST00000264426.14	c.229+18344A>G		intron_variant	Intron 2 of 15	1	NM_001083619.3	ENSP00000264426.9

Frequencies

GnomAD3 genomes AF: 0.409 AC: 62016 AN: 151812 Hom.: 14759 Cov.: 32

Gnomad AFR AF: 0.670

Gnomad AMI AF: 0.353

Gnomad AMR AF: 0.292

Gnomad ASJ AF: 0.297

Gnomad EAS AF: 0.175

Gnomad SAS AF: 0.270

Gnomad FIN AF: 0.342

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.321

Gnomad OTH AF: 0.379

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

GnomAD4 genome AF: 0.409 AC: 62119 AN: 151932 Hom.: 14802 Cov.: 32 AF XY: 0.405 AC XY: 30050 AN XY: 74250

African (AFR) AF: 0.670 AC: 27770 AN: 41438

American (AMR) AF: 0.291 AC: 4440 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.297 AC: 1029 AN: 3470

East Asian (EAS) AF: 0.175 AC: 904 AN: 5164

South Asian (SAS) AF: 0.271 AC: 1305 AN: 4816

European-Finnish (FIN) AF: 0.342 AC: 3609 AN: 10548

Middle Eastern (MID) AF: 0.401 AC: 117 AN: 292

European-Non Finnish (NFE) AF: 0.321 AC: 21825 AN: 67942

Other (OTH) AF: 0.379 AC: 799 AN: 2110

Alfa AF: 0.376 Hom.: 1813

Bravo AF: 0.417

Asia WGS AF: 0.283 AC: 982 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.10
DANN	Benign	0.36
PhyloP100		-1.0
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: rs11946396; hg19: chr4-158161303;