chr4-157221668-G-T

Variant names:

• chr4-157221668-G-T
• rs79163474
• ENST00000393815.6:c.-52G>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001083619.3(GRIA2):​c.90G>T​(p.Gly30Gly) 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
• 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: Ambry Genetics, G2P, ClinGen, Illumina, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1470 AD gene.

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.90G>T	p.Gly30Gly	splice_region synonymous	Exon 2 of 16	NP_001077088.2	P42262-1
	GRIA2	NM_001083620.3		c.-52G>T		splice_region	Exon 2 of 16	NP_001077089.2	P42262-4
	GRIA2	NM_001379000.3		c.-52G>T		splice_region	Exon 2 of 16	NP_001365929.3	A0A994J4F1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIA2	ENST00000393815.6	TSL:1	c.-52G>T		splice_region	Exon 2 of 16	ENSP00000377403.2	P42262-4
	GRIA2	ENST00000264426.14	TSL:1 MANE Select	c.90G>T	p.Gly30Gly	splice_region synonymous	Exon 2 of 16	ENSP00000264426.9	P42262-1
	GRIA2	ENST00000296526.12	TSL:1	c.90G>T	p.Gly30Gly	splice_region synonymous	Exon 2 of 16	ENSP00000296526.7	P42262-2

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

GnomAD2 exomes AF: 0.00924 AC: 2322 AN: 251258 AF XY: 0.00947

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 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

African (AFR) AF: 0.00227 AC: 76 AN: 33480

American (AMR) AF: 0.00879 AC: 393 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.000345 AC: 9 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00236 AC: 204 AN: 86258

European-Finnish (FIN) AF: 0.0128 AC: 685 AN: 53406

Middle Eastern (MID) AF: 0.00520 AC: 30 AN: 5768

European-Non Finnish (NFE) AF: 0.0157 AC: 17501 AN: 1111838

Other (OTH) AF: 0.0126 AC: 762 AN: 60392

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

African (AFR) AF: 0.00277 AC: 115 AN: 41564

American (AMR) AF: 0.0101 AC: 154 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00248 AC: 12 AN: 4830

European-Finnish (FIN) AF: 0.0163 AC: 173 AN: 10612

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0145 AC: 989 AN: 68024

Other (OTH) AF: 0.0118 AC: 25 AN: 2114

Alfa AF: 0.0119 Hom.: 57

Bravo AF: 0.00935

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0146

EpiControl AF: 0.0155

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	15
DANN	Benign	0.81
PhyloP100		0.74
PromoterAI		-0.16	Neutral
Mutation Taster		=50/50

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

Other links and lift over

dbSNP: rs79163474; hg19: chr4-158142820;