rs4302506

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr4-157317678-T-A
• chr4-157317678-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001083619.3(GRIA2):​c.687T>A​(p.His229Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000937 in 1,066,898 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H229R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 9.4e-7 (0 hom.)
• Consequence: GRIA2 NM_001083619.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.58
• 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: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, G2P, Illumina

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the GRIA2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 23 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: 4.5573 (above the threshold of 3.09). Trascript score misZ: 5.479 (above the threshold of 3.09). GenCC associations: The gene is linked to neurodevelopmental disorder with language impairment and behavioral abnormalities.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIA2	NM_001083619.3	c.687T>A	p.His229Gln	missense_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>A	p.His229Gln	missense_variant	Exon 5 of 16	1	NM_001083619.3	ENSP00000264426.9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 9.37e-7 AC: 1 AN: 1066898 Hom.: 0 Cov.: 14 AF XY: 0.00 AC XY: 0 AN XY: 547780

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26144

American (AMR) AF: 0.00 AC: 0 AN: 42316

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23192

East Asian (EAS) AF: 0.00 AC: 0 AN: 36662

South Asian (SAS) AF: 0.00 AC: 0 AN: 73682

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51962

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5006

European-Non Finnish (NFE) AF: 0.00000131 AC: 1 AN: 761166

Other (OTH) AF: 0.00 AC: 0 AN: 46768

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	.;.;.;.;T;T
Eigen	Benign	0.13
Eigen_PC	Benign	0.11
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	.;D;D;D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.69	D;D;D;D;D;D
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.6	.;.;L;L;L;.
PhyloP100		1.6
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.5	N;N;.;N;N;N
REVEL	Benign	0.23
Sift	Uncertain	0.016	D;D;.;D;D;D
Sift4G	Benign	0.16	T;T;.;T;T;D
Polyphen		0.73, 1.0	.;.;.;P;D;.
Vest4		0.68
MutPred		0.52		.;.;Gain of catalytic residue at H229 (P = 0.0177);Gain of catalytic residue at H229 (P = 0.0177);Gain of catalytic residue at H229 (P = 0.0177);.;
MVP		0.66
MPC		0.88
ClinPred		0.83	D
GERP RS		1.4
Varity_R		0.51
gMVP		0.86
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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;