rs76224028

Variant names:

• chr5-161854179-A-G
• rs76224028
• NM_001127644.2:c.96A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001127644.2(GABRA1):​c.96A>G​(p.Gln32Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,603,334 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0098 (30 hom., cov: 32)
  • Exomes 𝑓: 0.00098 (11 hom.)
• Consequence: GABRA1 NM_001127644.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 3.42
• Publications: 4 publications found

Genes affected

GABRA1 (HGNC:4075): (gamma-aminobutyric acid type A receptor subunit alpha1) This gene encodes a gamma-aminobutyric acid (GABA) receptor. 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. GABA-A receptors are pentameric, consisting of proteins from several subunit classes: alpha, beta, gamma, delta and rho. Mutations in this gene cause juvenile myoclonic epilepsy and childhood absence epilepsy type 4. Multiple transcript variants encoding the same protein have been identified for this gene. [provided by RefSeq, Jul 2008]

GABRA1 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 19

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• epilepsy, idiopathic generalized, susceptibility to, 13

  Inheritance: AD Classification: STRONG Submitted by: G2P
• Dravet syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• juvenile myoclonic epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 5-161854179-A-G is Benign according to our data. Variant chr5-161854179-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 129125.
• BP7: Synonymous conserved (PhyloP=3.42 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00984 (1494/151854) while in subpopulation AFR AF = 0.0335 (1392/41520). AF 95% confidence interval is 0.0321. There are 30 homozygotes in GnomAd4. There are 697 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1494 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127644.2. 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
	GABRA1	NM_001127644.2	MANE Select	c.96A>G	p.Gln32Gln	synonymous	Exon 3 of 10	NP_001121116.1
	GABRA1	NM_000806.5		c.96A>G	p.Gln32Gln	synonymous	Exon 4 of 11	NP_000797.2
	GABRA1	NM_001127643.2		c.96A>G	p.Gln32Gln	synonymous	Exon 4 of 11	NP_001121115.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA1	ENST00000393943.10	TSL:1 MANE Select	c.96A>G	p.Gln32Gln	synonymous	Exon 3 of 10	ENSP00000377517.4
	GABRA1	ENST00000023897.10	TSL:1	c.96A>G	p.Gln32Gln	synonymous	Exon 4 of 11	ENSP00000023897.6
	GABRA1	ENST00000428797.7	TSL:1	c.96A>G	p.Gln32Gln	synonymous	Exon 4 of 11	ENSP00000393097.2

Frequencies

GnomAD3 genomes AF: 0.00981 AC: 1488 AN: 151736 Hom.: 30 Cov.: 32

Gnomad AFR AF: 0.0335

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00441

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000148

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00255 AC: 638 AN: 250520 AF XY: 0.00195

Gnomad AFR exome AF: 0.0344

Gnomad AMR exome AF: 0.00151

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000186

Gnomad OTH exome AF: 0.000982

GnomAD4 exome AF: 0.000982 AC: 1426 AN: 1451480 Hom.: 11 Cov.: 28 AF XY: 0.000874 AC XY: 632 AN XY: 722802

African (AFR) AF: 0.0332 AC: 1100 AN: 33152

American (AMR) AF: 0.00161 AC: 72 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25996

East Asian (EAS) AF: 0.00 AC: 0 AN: 39586

South Asian (SAS) AF: 0.0000930 AC: 8 AN: 85988

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.000870 AC: 5 AN: 5744

European-Non Finnish (NFE) AF: 0.000110 AC: 121 AN: 1102926

Other (OTH) AF: 0.00200 AC: 120 AN: 60014

GnomAD4 genome AF: 0.00984 AC: 1494 AN: 151854 Hom.: 30 Cov.: 32 AF XY: 0.00939 AC XY: 697 AN XY: 74246

African (AFR) AF: 0.0335 AC: 1392 AN: 41520

American (AMR) AF: 0.00440 AC: 67 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000148 AC: 10 AN: 67720

Other (OTH) AF: 0.0114 AC: 24 AN: 2106

Alfa AF: 0.00324 Hom.: 7

Bravo AF: 0.0108

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000219

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	1	-	Epilepsy, idiopathic generalized, susceptibility to, 13 (1)
-	-	1	Idiopathic generalized epilepsy;C1970160:Epilepsy, childhood absence 4;C4013473:Epilepsy, idiopathic generalized, susceptibility to, 13 (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_noAF	Benign	-0.49
CADD	Benign	6.3
DANN	Benign	0.59
PhyloP100		3.4
Mutation Taster		=100/0	polymorphism

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: rs76224028; hg19: chr5-161281185;