chr4-157364445-T-C

Variant names:

• chr4-157364445-T-C
• rs4403097
• NM_001083619.3:c.*1014T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001083619.3(GRIA2):​c.*1014T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.451 in 151,356 control chromosomes in the GnomAD database, including 18,679 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.45 (18666 hom., cov: 31)
  • Exomes 𝑓: 0.59 (13 hom.)
• Consequence: GRIA2 NM_001083619.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.19
• Publications: 10 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.656 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIA2	NM_001083619.3	MANE Select	c.*1014T>C		3_prime_UTR	Exon 16 of 16	NP_001077088.2
	GRIA2	NM_000826.6		c.*1014T>C		3_prime_UTR	Exon 16 of 16	NP_000817.5
	GRIA2	NM_001083620.3		c.*1014T>C		3_prime_UTR	Exon 16 of 16	NP_001077089.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIA2	ENST00000264426.14	TSL:1 MANE Select	c.*1014T>C		3_prime_UTR	Exon 16 of 16	ENSP00000264426.9
	GRIA2	ENST00000296526.12	TSL:1	c.*1014T>C		3_prime_UTR	Exon 16 of 16	ENSP00000296526.7
	GRIA2	ENST00000393815.6	TSL:1	c.*1014T>C		3_prime_UTR	Exon 16 of 16	ENSP00000377403.2

Frequencies

GnomAD3 genomes AF: 0.451 AC: 68238 AN: 151148 Hom.: 18667 Cov.: 31

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.482

Gnomad AMR AF: 0.580

Gnomad ASJ AF: 0.568

Gnomad EAS AF: 0.674

Gnomad SAS AF: 0.656

Gnomad FIN AF: 0.554

Gnomad MID AF: 0.565

Gnomad NFE AF: 0.570

Gnomad OTH AF: 0.479

GnomAD4 exome AF: 0.589 AC: 53 AN: 90 Hom.: 13 Cov.: 0 AF XY: 0.567 AC XY: 34 AN XY: 60

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.591 AC: 52 AN: 88

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AF: 0.500 AC: 1 AN: 2

GnomAD4 genome AF: 0.451 AC: 68241 AN: 151266 Hom.: 18666 Cov.: 31 AF XY: 0.457 AC XY: 33754 AN XY: 73890

African (AFR) AF: 0.120 AC: 4952 AN: 41426

American (AMR) AF: 0.581 AC: 8772 AN: 15106

Ashkenazi Jewish (ASJ) AF: 0.568 AC: 1969 AN: 3464

East Asian (EAS) AF: 0.674 AC: 3447 AN: 5112

South Asian (SAS) AF: 0.654 AC: 3151 AN: 4816

European-Finnish (FIN) AF: 0.554 AC: 5739 AN: 10352

Middle Eastern (MID) AF: 0.569 AC: 164 AN: 288

European-Non Finnish (NFE) AF: 0.570 AC: 38594 AN: 67680

Other (OTH) AF: 0.480 AC: 1013 AN: 2110

Alfa AF: 0.478 Hom.: 3044

Bravo AF: 0.437

Asia WGS AF: 0.606 AC: 2090 AN: 3446

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.3
DANN	Benign	0.64
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4403097; hg19: chr4-158285597;