rs587777307

Variant names:

• chr5-161890945-G-A
• rs587777307
• NM_001127644.2:c.751G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_001127644.2(GABRA1):​c.751G>A​(p.Gly251Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV003439308: Experimental studies have shown that this missense change affects GABRA1 function (PMID:24623842).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G251R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GABRA1 NM_001127644.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.88
• Publications: 6 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 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV003439308: Experimental studies have shown that this missense change affects GABRA1 function (PMID: 24623842).
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001127644.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-161890946-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 419523.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.899
• PP5: Variant 5-161890945-G-A is Pathogenic according to our data. Variant chr5-161890945-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 127073.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.751G>A	p.Gly251Ser	missense	Exon 8 of 10	NP_001121116.1	P14867
	GABRA1	NM_000806.5		c.751G>A	p.Gly251Ser	missense	Exon 9 of 11	NP_000797.2	A8K177
	GABRA1	NM_001127643.2		c.751G>A	p.Gly251Ser	missense	Exon 9 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.751G>A	p.Gly251Ser	missense	Exon 8 of 10	ENSP00000377517.4	P14867
	GABRA1	ENST00000023897.10	TSL:1	c.751G>A	p.Gly251Ser	missense	Exon 9 of 11	ENSP00000023897.6	P14867
	GABRA1	ENST00000428797.7	TSL:1	c.751G>A	p.Gly251Ser	missense	Exon 9 of 11	ENSP00000393097.2	P14867

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Developmental and epileptic encephalopathy, 19 (1)
1	-	-	Idiopathic generalized epilepsy;C1970160:Epilepsy, childhood absence 4;C4013473:Epilepsy, idiopathic generalized, susceptibility to, 13 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Benign	2.0	M
PhyloP100		9.9
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.93	P
Vest4		0.94
MutPred		0.67		Loss of catalytic residue at I250 (P = 0.1308)
MVP		0.99
MPC		1.8
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.94
gMVP		0.95
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.20		Position offset: -47

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587777307; hg19: chr5-161317951;