4-157317678-T-C

Variant names:

• chr4-157317678-T-C
• rs4302506
• NM_001083619.3:c.687T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001083619.3(GRIA2):​c.687T>C​(p.His229His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.632 in 1,208,880 control chromosomes in the GnomAD database, including 246,102 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (30113 hom., cov: 32)
  • Exomes 𝑓: 0.63 (215989 hom.)
• Consequence: GRIA2 NM_001083619.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.58
• Publications: 24 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 4-157317678-T-C is Benign according to our data. Variant chr4-157317678-T-C is described in ClinVar as Benign. ClinVar VariationId is 1266895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.59 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.801 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIA2	NM_001083619.3	c.687T>C	p.His229His	synonymous_variant	Exon 5 of 16	ENST00000264426.14	NP_001077088.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIA2	ENST00000264426.14	c.687T>C	p.His229His	synonymous_variant	Exon 5 of 16	1	NM_001083619.3	ENSP00000264426.9

Frequencies

GnomAD3 genomes AF: 0.624 AC: 94767 AN: 151796 Hom.: 30101 Cov.: 32

Gnomad AFR AF: 0.513

Gnomad AMI AF: 0.562

Gnomad AMR AF: 0.710

Gnomad ASJ AF: 0.642

Gnomad EAS AF: 0.821

Gnomad SAS AF: 0.724

Gnomad FIN AF: 0.647

Gnomad MID AF: 0.598

Gnomad NFE AF: 0.647

Gnomad OTH AF: 0.623

GnomAD2 exomes AF: 0.674 AC: 161742 AN: 240144 AF XY: 0.671

Gnomad AFR exome AF: 0.500

Gnomad AMR exome AF: 0.793

Gnomad ASJ exome AF: 0.650

Gnomad EAS exome AF: 0.812

Gnomad FIN exome AF: 0.642

Gnomad NFE exome AF: 0.637

Gnomad OTH exome AF: 0.646

GnomAD4 exome AF: 0.633 AC: 669281 AN: 1056966 Hom.: 215989 Cov.: 14 AF XY: 0.637 AC XY: 345672 AN XY: 542972

African (AFR) AF: 0.487 AC: 12615 AN: 25916

American (AMR) AF: 0.782 AC: 32969 AN: 42168

Ashkenazi Jewish (ASJ) AF: 0.640 AC: 14755 AN: 23062

East Asian (EAS) AF: 0.839 AC: 30683 AN: 36574

South Asian (SAS) AF: 0.712 AC: 52099 AN: 73224

European-Finnish (FIN) AF: 0.640 AC: 33143 AN: 51768

Middle Eastern (MID) AF: 0.578 AC: 2881 AN: 4984

European-Non Finnish (NFE) AF: 0.612 AC: 460943 AN: 752926

Other (OTH) AF: 0.630 AC: 29193 AN: 46344

GnomAD4 genome AF: 0.624 AC: 94811 AN: 151914 Hom.: 30113 Cov.: 32 AF XY: 0.627 AC XY: 46563 AN XY: 74222

African (AFR) AF: 0.513 AC: 21235 AN: 41408

American (AMR) AF: 0.711 AC: 10845 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.642 AC: 2223 AN: 3462

East Asian (EAS) AF: 0.822 AC: 4244 AN: 5164

South Asian (SAS) AF: 0.722 AC: 3482 AN: 4820

European-Finnish (FIN) AF: 0.647 AC: 6808 AN: 10530

Middle Eastern (MID) AF: 0.605 AC: 178 AN: 294

European-Non Finnish (NFE) AF: 0.647 AC: 43966 AN: 67958

Other (OTH) AF: 0.624 AC: 1320 AN: 2114

Alfa AF: 0.628 Hom.: 13748

Bravo AF: 0.622

Asia WGS AF: 0.730 AC: 2530 AN: 3464

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

May 11, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	9.3
DANN	Benign	0.61
PhyloP100		1.6
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs4302506; hg19: chr4-158238830; COSMIC: COSV52388677; COSMIC: COSV52388677;