NM_001083619.3:c.258delT

Variant names:

• chr4-157303579-AT-A
• rs2126866545
• NM_001083619.3:c.258delT

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001083619.3(GRIA2):​c.258delT​(p.Tyr86fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GRIA2 NM_001083619.3 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.986
• Publications: 0 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-157303579-AT-A is Pathogenic according to our data. Variant chr4-157303579-AT-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1174085.Status of the report is no_assertion_criteria_provided, 0 stars.

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.258delT	p.Tyr86fs	frameshift	Exon 3 of 16	NP_001077088.2	P42262-1
	GRIA2	NM_000826.6		c.258delT	p.Tyr86fs	frameshift	Exon 3 of 16	NP_000817.5	P42262-2
	GRIA2	NM_001083620.3		c.117delT	p.Tyr39fs	frameshift	Exon 3 of 16	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.258delT	p.Tyr86fs	frameshift	Exon 3 of 16	ENSP00000264426.9	P42262-1
	GRIA2	ENST00000296526.12	TSL:1	c.258delT	p.Tyr86fs	frameshift	Exon 3 of 16	ENSP00000296526.7	P42262-2
	GRIA2	ENST00000393815.6	TSL:1	c.117delT	p.Tyr39fs	frameshift	Exon 3 of 16	ENSP00000377403.2	P42262-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Neurodevelopmental disorder with language impairment and behavioral abnormalities (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.99

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: rs2126866545; hg19: chr4-158224731;