4-46250049-C-T

Variant names:

• chr4-46250049-C-T
• rs573400
• NM_000807.4:c.*259G>A

Variant summary

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

The NM_000807.4(GABRA2):​c.*259G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.611 in 356,358 control chromosomes in the GnomAD database, including 67,838 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 0.63 (30291 hom., cov: 31)
  • Exomes 𝑓: 0.60 (37547 hom.)
• Consequence: GABRA2 NM_000807.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.265
• Publications: 17 publications found

Genes affected

GABRA2 (HGNC:4076): (gamma-aminobutyric acid type A receptor subunit alpha2) GABA is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABA-A receptors, which are ligand-gated chloride channels. Chloride conductance of these channels can be modulated by agents such as benzodiazepines that bind to the GABA-A receptor. At least 16 distinct subunits of GABA-A receptors have been identified. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2013]

GABRA2 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 78

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.758 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000807.4. 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
	GABRA2	NM_000807.4	MANE Select	c.*259G>A		3_prime_UTR	Exon 10 of 10	NP_000798.2	P47869-1
	GABRA2	NM_001330690.2		c.*259G>A		3_prime_UTR	Exon 11 of 11	NP_001317619.1	E9PBQ7
	GABRA2	NM_001377144.1		c.*259G>A		3_prime_UTR	Exon 11 of 11	NP_001364073.1	E9PBQ7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA2	ENST00000381620.9	TSL:1 MANE Select	c.*259G>A		3_prime_UTR	Exon 10 of 10	ENSP00000371033.4	P47869-1
	GABRA2	ENST00000863565.1		c.*259G>A		3_prime_UTR	Exon 11 of 11	ENSP00000533624.1
	GABRA2	ENST00000356504.5	TSL:2	c.*259G>A		3_prime_UTR	Exon 9 of 9	ENSP00000348897.1	P47869-1

Frequencies

GnomAD3 genomes AF: 0.626 AC: 94668 AN: 151176 Hom.: 30273 Cov.: 31

Gnomad AFR AF: 0.737

Gnomad AMI AF: 0.618

Gnomad AMR AF: 0.554

Gnomad ASJ AF: 0.695

Gnomad EAS AF: 0.550

Gnomad SAS AF: 0.778

Gnomad FIN AF: 0.599

Gnomad MID AF: 0.649

Gnomad NFE AF: 0.570

Gnomad OTH AF: 0.629

GnomAD4 exome AF: 0.600 AC: 122986 AN: 205062 Hom.: 37547 Cov.: 2 AF XY: 0.605 AC XY: 64175 AN XY: 106060

African (AFR) AF: 0.730 AC: 4653 AN: 6374

American (AMR) AF: 0.536 AC: 4271 AN: 7970

Ashkenazi Jewish (ASJ) AF: 0.695 AC: 5156 AN: 7414

East Asian (EAS) AF: 0.620 AC: 10512 AN: 16956

South Asian (SAS) AF: 0.764 AC: 9203 AN: 12042

European-Finnish (FIN) AF: 0.598 AC: 7072 AN: 11832

Middle Eastern (MID) AF: 0.739 AC: 739 AN: 1000

European-Non Finnish (NFE) AF: 0.573 AC: 73532 AN: 128404

Other (OTH) AF: 0.600 AC: 7848 AN: 13070

GnomAD4 genome AF: 0.626 AC: 94726 AN: 151296 Hom.: 30291 Cov.: 31 AF XY: 0.627 AC XY: 46318 AN XY: 73918

African (AFR) AF: 0.736 AC: 30473 AN: 41376

American (AMR) AF: 0.553 AC: 8373 AN: 15132

Ashkenazi Jewish (ASJ) AF: 0.695 AC: 2399 AN: 3454

East Asian (EAS) AF: 0.549 AC: 2799 AN: 5094

South Asian (SAS) AF: 0.778 AC: 3741 AN: 4806

European-Finnish (FIN) AF: 0.599 AC: 6313 AN: 10540

Middle Eastern (MID) AF: 0.633 AC: 186 AN: 294

European-Non Finnish (NFE) AF: 0.570 AC: 38554 AN: 67586

Other (OTH) AF: 0.630 AC: 1324 AN: 2102

Alfa AF: 0.583 Hom.: 13352

Bravo AF: 0.621

Asia WGS AF: 0.652 AC: 2267 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.072
DANN	Benign	0.41
PhyloP100		-0.27
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: rs573400; hg19: chr4-46252066;