4-157221668-G-T

Position:

• chr4-157221668-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001083619.3(GRIA2):​c.90G>T​(p.Gly30=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0131 in 1,613,956 control chromosomes in the GnomAD database, including 175 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0097 (9 hom., cov: 32)
  • Exomes 𝑓: 0.013 (166 hom.)
• Consequence: GRIA2 NM_001083619.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.0004785
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.736

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 Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 4-157221668-G-T is Benign according to our data. Variant chr4-157221668-G-T is described in ClinVar as [Benign]. Clinvar id is 780113.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.736 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00965 (1470/152286) while in subpopulation NFE AF= 0.0145 (989/68024). AF 95% confidence interval is 0.0138. There are 9 homozygotes in gnomad4. There are 702 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1470 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIA2	NM_001083619.3	c.90G>T	p.Gly30=	splice_region_variant, synonymous_variant	2/16	ENST00000264426.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIA2	ENST00000264426.14	c.90G>T	p.Gly30=	splice_region_variant, synonymous_variant	2/16	1	NM_001083619.3	P4

Frequencies

GnomAD3 genomes AF: 0.00967 AC: 1472 AN: 152168 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00280

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0101

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.0163

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0146

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.00924 AC: 2322 AN: 251258 Hom.: 25 AF XY: 0.00947 AC XY: 1286 AN XY: 135800

Gnomad AFR exome AF: 0.00240

Gnomad AMR exome AF: 0.00813

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00225

Gnomad FIN exome AF: 0.0147

Gnomad NFE exome AF: 0.0136

Gnomad OTH exome AF: 0.0109

GnomAD4 exome AF: 0.0135 AC: 19660 AN: 1461670 Hom.: 166 Cov.: 31 AF XY: 0.0133 AC XY: 9637 AN XY: 727162

Gnomad4 AFR exome AF: 0.00227

Gnomad4 AMR exome AF: 0.00879

Gnomad4 ASJ exome AF: 0.000345

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00236

Gnomad4 FIN exome AF: 0.0128

Gnomad4 NFE exome AF: 0.0157

Gnomad4 OTH exome AF: 0.0126

GnomAD4 genome AF: 0.00965 AC: 1470 AN: 152286 Hom.: 9 Cov.: 32 AF XY: 0.00943 AC XY: 702 AN XY: 74454

Gnomad4 AFR AF: 0.00277

Gnomad4 AMR AF: 0.0101

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00248

Gnomad4 FIN AF: 0.0163

Gnomad4 NFE AF: 0.0145

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.0124 Hom.: 30

Bravo AF: 0.00935

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0146

EpiControl AF: 0.0155

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	GRIA2: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	15
DANN	Benign	0.81

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00048
dbscSNV1_RF	Benign	0.028
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: rs79163474; hg19: chr4-158142820;