5-161878065-C-T

Variant names:

• chr5-161878065-C-T
• rs6878494
• NM_001127644.2:c.559+2423C>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.559+2423C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.513 in 152,006 control chromosomes in the GnomAD database, including 20,833 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 0.51 (20833 hom., cov: 33)
• Consequence: GABRA1 NM_001127644.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.276
• Publications: 2 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=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.633 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.559+2423C>T		intron	N/A	NP_001121116.1	P14867
	GABRA1	NM_000806.5		c.559+2423C>T		intron	N/A	NP_000797.2	A8K177
	GABRA1	NM_001127643.2		c.559+2423C>T		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.559+2423C>T		intron	N/A	ENSP00000377517.4	P14867
	GABRA1	ENST00000023897.10	TSL:1	c.559+2423C>T		intron	N/A	ENSP00000023897.6	P14867
	GABRA1	ENST00000428797.7	TSL:1	c.559+2423C>T		intron	N/A	ENSP00000393097.2	P14867

Frequencies

GnomAD3 genomes AF: 0.513 AC: 77972 AN: 151888 Hom.: 20800 Cov.: 33

Gnomad AFR AF: 0.628

Gnomad AMI AF: 0.493

Gnomad AMR AF: 0.426

Gnomad ASJ AF: 0.488

Gnomad EAS AF: 0.651

Gnomad SAS AF: 0.616

Gnomad FIN AF: 0.518

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.446

Gnomad OTH AF: 0.515

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.513 AC: 78040 AN: 152006 Hom.: 20833 Cov.: 33 AF XY: 0.517 AC XY: 38380 AN XY: 74288

African (AFR) AF: 0.628 AC: 26052 AN: 41454

American (AMR) AF: 0.426 AC: 6504 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.488 AC: 1690 AN: 3466

East Asian (EAS) AF: 0.651 AC: 3369 AN: 5174

South Asian (SAS) AF: 0.614 AC: 2964 AN: 4824

European-Finnish (FIN) AF: 0.518 AC: 5461 AN: 10538

Middle Eastern (MID) AF: 0.551 AC: 162 AN: 294

European-Non Finnish (NFE) AF: 0.446 AC: 30291 AN: 67976

Other (OTH) AF: 0.520 AC: 1097 AN: 2110

Alfa AF: 0.464 Hom.: 65969

Bravo AF: 0.514

Asia WGS AF: 0.657 AC: 2283 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	5.1
DANN	Benign	0.54
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: rs6878494; hg19: chr5-161305071;