4-157221940-A-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001083619.3(GRIA2):​c.229+133A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 29)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 618678 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 325142

African (AFR) AF: 0.00 AC: 0 AN: 17282

American (AMR) AF: 0.00 AC: 0 AN: 31752

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16756

East Asian (EAS) AF: 0.00 AC: 0 AN: 33962

South Asian (SAS) AF: 0.00 AC: 0 AN: 57596

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37522

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2356

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 389200

Other (OTH) AF: 0.00 AC: 0 AN: 32252

GnomAD4 genome Cov.: 29

Alfa AF: 0.00 Hom.: 14583

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	20
DANN	Benign	0.87
PhyloP100		2.1
PromoterAI		0.00060	Neutral

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;