rs11728471

Variant names:

• chr4-157351628-C-T
• rs11728471
• NM_001083619.3:c.2044-8268C>T

Variant summary

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

The NM_001083619.3(GRIA2):​c.2044-8268C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.075 in 152,220 control chromosomes in the GnomAD database, including 573 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 0.075 (573 hom., cov: 32)
• Consequence: GRIA2 NM_001083619.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0260
• 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=-0.95).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIA2	NM_001083619.3	c.2044-8268C>T		intron_variant	Intron 12 of 15	ENST00000264426.14	NP_001077088.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIA2	ENST00000264426.14	c.2044-8268C>T		intron_variant	Intron 12 of 15	1	NM_001083619.3	ENSP00000264426.9

Frequencies

GnomAD3 genomes AF: 0.0750 AC: 11402 AN: 152102 Hom.: 572 Cov.: 32

Gnomad AFR AF: 0.0172

Gnomad AMI AF: 0.194

Gnomad AMR AF: 0.0569

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.00232

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.146

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.0674

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

GnomAD4 genome AF: 0.0750 AC: 11413 AN: 152220 Hom.: 573 Cov.: 32 AF XY: 0.0770 AC XY: 5729 AN XY: 74414

African (AFR) AF: 0.0171 AC: 712 AN: 41554

American (AMR) AF: 0.0569 AC: 871 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 378 AN: 3466

East Asian (EAS) AF: 0.00232 AC: 12 AN: 5168

South Asian (SAS) AF: 0.122 AC: 589 AN: 4826

European-Finnish (FIN) AF: 0.146 AC: 1547 AN: 10584

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.102 AC: 6967 AN: 68002

Other (OTH) AF: 0.0662 AC: 140 AN: 2114

Alfa AF: 0.0866 Hom.: 130

Bravo AF: 0.0646

Asia WGS AF: 0.0590 AC: 204 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	2.0
DANN	Benign	0.20
PhyloP100		-0.026
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: rs11728471; hg19: chr4-158272780;