rs2279020

Variant names:

• chr5-161895883-G-A
• rs2279020
• NM_001127644.2:c.1059+15G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001127644.2(GABRA1):​c.1059+15G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.646 in 1,601,462 control chromosomes in the GnomAD database, including 336,405 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (30064 hom., cov: 32)
  • Exomes 𝑓: 0.65 (306341 hom.)
• Consequence: GABRA1 NM_001127644.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.302
• Publications: 44 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 5-161895883-G-A is Benign according to our data. Variant chr5-161895883-G-A is described in ClinVar as Benign. ClinVar VariationId is 93431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.693 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.1059+15G>A		intron	N/A	NP_001121116.1	P14867
	GABRA1	NM_000806.5		c.1059+15G>A		intron	N/A	NP_000797.2	A8K177
	GABRA1	NM_001127643.2		c.1059+15G>A		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.1059+15G>A		intron	N/A	ENSP00000377517.4	P14867
	GABRA1	ENST00000023897.10	TSL:1	c.1059+15G>A		intron	N/A	ENSP00000023897.6	P14867
	GABRA1	ENST00000428797.7	TSL:1	c.1059+15G>A		intron	N/A	ENSP00000393097.2	P14867

Frequencies

GnomAD3 genomes AF: 0.625 AC: 95015 AN: 151930 Hom.: 30025 Cov.: 32

Gnomad AFR AF: 0.599

Gnomad AMI AF: 0.573

Gnomad AMR AF: 0.704

Gnomad ASJ AF: 0.647

Gnomad EAS AF: 0.463

Gnomad SAS AF: 0.560

Gnomad FIN AF: 0.554

Gnomad MID AF: 0.573

Gnomad NFE AF: 0.652

Gnomad OTH AF: 0.625

GnomAD2 exomes AF: 0.621 AC: 156072 AN: 251212 AF XY: 0.616

Gnomad AFR exome AF: 0.600

Gnomad AMR exome AF: 0.716

Gnomad ASJ exome AF: 0.654

Gnomad EAS exome AF: 0.439

Gnomad FIN exome AF: 0.549

Gnomad NFE exome AF: 0.650

Gnomad OTH exome AF: 0.628

GnomAD4 exome AF: 0.648 AC: 939033 AN: 1449414 Hom.: 306341 Cov.: 30 AF XY: 0.644 AC XY: 465075 AN XY: 721866

African (AFR) AF: 0.595 AC: 19738 AN: 33198

American (AMR) AF: 0.714 AC: 31932 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.652 AC: 16994 AN: 26070

East Asian (EAS) AF: 0.479 AC: 18983 AN: 39624

South Asian (SAS) AF: 0.567 AC: 48754 AN: 86006

European-Finnish (FIN) AF: 0.556 AC: 29682 AN: 53360

Middle Eastern (MID) AF: 0.590 AC: 3383 AN: 5736

European-Non Finnish (NFE) AF: 0.665 AC: 731437 AN: 1100726

Other (OTH) AF: 0.636 AC: 38130 AN: 59982

GnomAD4 genome AF: 0.626 AC: 95111 AN: 152048 Hom.: 30064 Cov.: 32 AF XY: 0.622 AC XY: 46227 AN XY: 74286

African (AFR) AF: 0.599 AC: 24836 AN: 41464

American (AMR) AF: 0.704 AC: 10758 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.647 AC: 2245 AN: 3472

East Asian (EAS) AF: 0.463 AC: 2393 AN: 5170

South Asian (SAS) AF: 0.562 AC: 2710 AN: 4824

European-Finnish (FIN) AF: 0.554 AC: 5843 AN: 10556

Middle Eastern (MID) AF: 0.578 AC: 170 AN: 294

European-Non Finnish (NFE) AF: 0.652 AC: 44316 AN: 67968

Other (OTH) AF: 0.625 AC: 1317 AN: 2106

Alfa AF: 0.642 Hom.: 59315

Bravo AF: 0.634

Asia WGS AF: 0.531 AC: 1850 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Developmental and epileptic encephalopathy, 19 (1)
-	-	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	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.96
DANN	Benign	0.17
PhyloP100		0.30
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: rs2279020; hg19: chr5-161322889; COSMIC: COSV50100429; COSMIC: COSV50100429;