chr4-157221940-A-G

Variant names:

• chr4-157221940-A-G
• rs13138842
• NM_001083619.3:c.229+133A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_001083619.3(GRIA2):​c.229+133A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.813 in 769,922 control chromosomes in the GnomAD database, including 254,992 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 0.80 (48483 hom., cov: 29)
  • Exomes 𝑓: 0.82 (206509 hom.)
• Consequence: GRIA2 NM_001083619.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.05
• Publications: 5 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.825 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIA2	NM_001083619.3	c.229+133A>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+133A>G		intron_variant	Intron 2 of 15	1	NM_001083619.3	ENSP00000264426.9

Frequencies

GnomAD3 genomes AF: 0.798 AC: 121062 AN: 151668 Hom.: 48458 Cov.: 29

Gnomad AFR AF: 0.748

Gnomad AMI AF: 0.861

Gnomad AMR AF: 0.837

Gnomad ASJ AF: 0.829

Gnomad EAS AF: 0.839

Gnomad SAS AF: 0.829

Gnomad FIN AF: 0.816

Gnomad MID AF: 0.785

Gnomad NFE AF: 0.810

Gnomad OTH AF: 0.796

GnomAD4 exome AF: 0.816 AC: 504462 AN: 618132 Hom.: 206509 AF XY: 0.817 AC XY: 265470 AN XY: 324866

African (AFR) AF: 0.749 AC: 12924 AN: 17260

American (AMR) AF: 0.879 AC: 27900 AN: 31734

Ashkenazi Jewish (ASJ) AF: 0.823 AC: 13779 AN: 16740

East Asian (EAS) AF: 0.854 AC: 29001 AN: 33954

South Asian (SAS) AF: 0.844 AC: 48590 AN: 57572

European-Finnish (FIN) AF: 0.813 AC: 30492 AN: 37498

Middle Eastern (MID) AF: 0.791 AC: 1859 AN: 2350

European-Non Finnish (NFE) AF: 0.807 AC: 313948 AN: 388804

Other (OTH) AF: 0.806 AC: 25969 AN: 32220

GnomAD4 genome AF: 0.798 AC: 121133 AN: 151790 Hom.: 48483 Cov.: 29 AF XY: 0.799 AC XY: 59225 AN XY: 74142

African (AFR) AF: 0.747 AC: 30939 AN: 41418

American (AMR) AF: 0.837 AC: 12774 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.829 AC: 2878 AN: 3470

East Asian (EAS) AF: 0.839 AC: 4256 AN: 5072

South Asian (SAS) AF: 0.828 AC: 3975 AN: 4798

European-Finnish (FIN) AF: 0.816 AC: 8622 AN: 10564

Middle Eastern (MID) AF: 0.779 AC: 229 AN: 294

European-Non Finnish (NFE) AF: 0.810 AC: 55007 AN: 67900

Other (OTH) AF: 0.794 AC: 1668 AN: 2100

Alfa AF: 0.797 Hom.: 14583

Bravo AF: 0.798

Asia WGS AF: 0.810 AC: 2815 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	20
DANN	Benign	0.73
PhyloP100		2.1
PromoterAI		0.098	Neutral
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: rs13138842; hg19: chr4-158143092;