4-157221056-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001083619.3(GRIA2):c.14T>C(p.Met5Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000211 in 1,422,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M5L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GRIA2 NM_001083619.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.82

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, GRIA2
• BP4: Computational evidence support a benign effect (MetaRNN=0.1587322).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIA2	NM_001083619.3	c.14T>C	p.Met5Thr	missense_variant	1/16	ENST00000264426.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIA2	ENST00000264426.14	c.14T>C	p.Met5Thr	missense_variant	1/16	1	NM_001083619.3	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251350 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135860

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000211 AC: 3 AN: 1422190 Hom.: 0 Cov.: 26 AF XY: 0.00000282 AC XY: 2 AN XY: 710192

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000351

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodevelopmental disorder with language impairment and behavioral abnormalities Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jan 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	21
Dann	Benign	0.92
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.069
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.72	T;T;T;T;T
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.16	T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-2.9	D;N;.;N;N
REVEL	Benign	0.17
Sift	Benign	0.063	T;T;.;T;T
Sift4G	Benign	0.81	T;T;.;T;T
Polyphen		0.0, 0.0040	.;.;.;B;B
Vest4		0.65, 0.64
MutPred		0.53		Loss of stability (P = 0.0186);Loss of stability (P = 0.0186);Loss of stability (P = 0.0186);Loss of stability (P = 0.0186);Loss of stability (P = 0.0186);
MVP		0.54
MPC		0.72
ClinPred		0.16	T
GERP RS		5.5
Varity_R		0.18
gMVP		0.84

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

Publications

LitVar

Other links and lift over

dbSNP: rs1368880258; hg19: chr4-158142208;