rs4340950

Variant names:

• chr5-161853637-A-G
• rs4340950
• NM_001127644.2:c.75-521A>G

Your query was ambiguous. Multiple possible variants found:

• chr5-161853637-A-G
• chr5-161853637-A-T

Variant summary

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

The NM_001127644.2(GABRA1):​c.75-521A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.147 in 151,882 control chromosomes in the GnomAD database, including 1,963 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 0.15 (1963 hom., cov: 32)
  • Exomes 𝑓: 0.056 (0 hom.)
• Consequence: GABRA1 NM_001127644.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.798
• Publications: 0 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• epilepsy

  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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.267 is higher than 0.05.

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.75-521A>G		intron	N/A	NP_001121116.1	P14867
	GABRA1	NM_000806.5		c.75-521A>G		intron	N/A	NP_000797.2	A8K177
	GABRA1	NM_001127643.2		c.75-521A>G		intron	N/A	NP_001121115.1	P14867

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA1	ENST00000393943.10	TSL:1 MANE Select	c.75-521A>G		intron	N/A	ENSP00000377517.4	P14867
	GABRA1	ENST00000023897.10	TSL:1	c.75-521A>G		intron	N/A	ENSP00000023897.6	P14867
	GABRA1	ENST00000428797.7	TSL:1	c.75-521A>G		intron	N/A	ENSP00000393097.2	P14867

Frequencies

GnomAD3 genomes AF: 0.147 AC: 22311 AN: 151692 Hom.: 1962 Cov.: 32

Gnomad AFR AF: 0.222

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.0823

Gnomad ASJ AF: 0.106

Gnomad EAS AF: 0.279

Gnomad SAS AF: 0.223

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.110

Gnomad OTH AF: 0.130

GnomAD4 exome AF: 0.0556 AC: 4 AN: 72 Hom.: 0 Cov.: 0 AF XY: 0.0652 AC XY: 3 AN XY: 46

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.250 AC: 1 AN: 4

European-Finnish (FIN) AF: 0.500 AC: 1 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0333 AC: 2 AN: 60

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.147 AC: 22315 AN: 151810 Hom.: 1963 Cov.: 32 AF XY: 0.149 AC XY: 11043 AN XY: 74222

African (AFR) AF: 0.222 AC: 9185 AN: 41464

American (AMR) AF: 0.0822 AC: 1251 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 369 AN: 3466

East Asian (EAS) AF: 0.279 AC: 1441 AN: 5162

South Asian (SAS) AF: 0.223 AC: 1075 AN: 4822

European-Finnish (FIN) AF: 0.115 AC: 1222 AN: 10602

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.110 AC: 7429 AN: 67752

Other (OTH) AF: 0.128 AC: 270 AN: 2110

Alfa AF: 0.111 Hom.: 1168

Bravo AF: 0.148

Asia WGS AF: 0.227 AC: 785 AN: 3464

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	17
DANN	Benign	0.86
PhyloP100		0.80
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs4340950; hg19: chr5-161280643;