rs548583

Variant names:

• chr4-46261327-A-G
• rs548583
• ENST00000515082.5:c.*554T>C

Variant summary

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

The NM_001377155.1(GABRA2):​c.*554T>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 0.6 in 152,916 control chromosomes in the GnomAD database, including 27,860 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 0.60 (27740 hom., cov: 33)
  • Exomes 𝑓: 0.51 (120 hom.)
• Consequence: GABRA2 NM_001377155.1 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.278
• Publications: 9 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, Labcorp Genetics (formerly Invitae), G2P
• 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=-0.83).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.742 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001377155.1. 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.1059+599T>C		intron	N/A	NP_000798.2
	GABRA2	NM_001377155.1		c.*554T>C		3_prime_UTR	Exon 9 of 9	NP_001364084.1
	GABRA2	NM_001330690.2		c.1059+599T>C		intron	N/A	NP_001317619.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA2	ENST00000515082.5	TSL:1	c.*554T>C		3_prime_UTR	Exon 9 of 9	ENSP00000423840.1
	GABRA2	ENST00000381620.9	TSL:1 MANE Select	c.1059+599T>C		intron	N/A	ENSP00000371033.4
	GABRA2	ENST00000507069.5	TSL:3	c.1059+599T>C		intron	N/A	ENSP00000427603.1

Frequencies

GnomAD3 genomes AF: 0.600 AC: 91160 AN: 151848 Hom.: 27725 Cov.: 33

Gnomad AFR AF: 0.655

Gnomad AMI AF: 0.618

Gnomad AMR AF: 0.543

Gnomad ASJ AF: 0.693

Gnomad EAS AF: 0.550

Gnomad SAS AF: 0.762

Gnomad FIN AF: 0.585

Gnomad MID AF: 0.640

Gnomad NFE AF: 0.569

Gnomad OTH AF: 0.611

GnomAD4 exome AF: 0.508 AC: 483 AN: 950 Hom.: 120 Cov.: 0 AF XY: 0.525 AC XY: 274 AN XY: 522

African (AFR) AF: 0.750 AC: 3 AN: 4

American (AMR) AF: 0.489 AC: 88 AN: 180

Ashkenazi Jewish (ASJ) AF: 0.750 AC: 3 AN: 4

East Asian (EAS) AF: 0.444 AC: 8 AN: 18

South Asian (SAS) AF: 0.724 AC: 55 AN: 76

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.486 AC: 312 AN: 642

Other (OTH) AF: 0.538 AC: 14 AN: 26

GnomAD4 genome AF: 0.600 AC: 91214 AN: 151966 Hom.: 27740 Cov.: 33 AF XY: 0.601 AC XY: 44604 AN XY: 74268

African (AFR) AF: 0.655 AC: 27191 AN: 41502

American (AMR) AF: 0.543 AC: 8270 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.693 AC: 2403 AN: 3468

East Asian (EAS) AF: 0.550 AC: 2831 AN: 5150

South Asian (SAS) AF: 0.762 AC: 3675 AN: 4822

European-Finnish (FIN) AF: 0.585 AC: 6179 AN: 10564

Middle Eastern (MID) AF: 0.623 AC: 182 AN: 292

European-Non Finnish (NFE) AF: 0.569 AC: 38626 AN: 67914

Other (OTH) AF: 0.612 AC: 1293 AN: 2114

Alfa AF: 0.588 Hom.: 13501

Bravo AF: 0.593

Asia WGS AF: 0.642 AC: 2232 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.1
DANN	Benign	0.51
PhyloP100		0.28
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: rs548583; hg19: chr4-46263344;