rs879253748

Variant names:

• chr5-161897250-TC-T
• rs879253748
• NM_001127644.2:c.1200delC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Strong PS3 PM2 PP5_Moderate

The NM_001127644.2(GABRA1):​c.1200delC​(p.Lys401SerfsTer25) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV000292033: Functional studies for these variants could demonstrate a disrupted surface expression, hence leading to a change in subunit composition with reduction of GABA-A mediated inhibition resulting in a predisposition to seizures.".

• Frequency: Genomes: not found (cov: 32)
• Consequence: GABRA1 NM_001127644.2 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.612
• 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.125 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000292033: Functional studies for these variants could demonstrate a disrupted surface expression, hence leading to a change in subunit composition with reduction of GABA-A mediated inhibition resulting in a predisposition to seizures.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-161897250-TC-T is Pathogenic according to our data. Variant chr5-161897250-TC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 242830.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1200delC	p.Lys401SerfsTer25	frameshift	Exon 10 of 10	NP_001121116.1	P14867
	GABRA1	NM_000806.5		c.1200delC	p.Lys401SerfsTer25	frameshift	Exon 11 of 11	NP_000797.2	A8K177
	GABRA1	NM_001127643.2		c.1200delC	p.Lys401SerfsTer25	frameshift	Exon 11 of 11	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.1200delC	p.Lys401SerfsTer25	frameshift	Exon 10 of 10	ENSP00000377517.4	P14867
	GABRA1	ENST00000023897.10	TSL:1	c.1200delC	p.Lys401SerfsTer25	frameshift	Exon 11 of 11	ENSP00000023897.6	P14867
	GABRA1	ENST00000428797.7	TSL:1	c.1200delC	p.Lys401SerfsTer25	frameshift	Exon 11 of 11	ENSP00000393097.2	P14867

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Developmental and epileptic encephalopathy, 19 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.61
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs879253748; hg19: chr5-161324256;