rs587777364

Variant names:

• chr5-161882653-G-A
• rs587777364
• NM_001127644.2:c.655G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001127644.2(GABRA1):​c.655G>A​(p.Asp219Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as risk factor (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GABRA1 NM_001127644.2 missense
• Clinical Significance: risk factor no assertion criteria provided O:1
• Conservation: PhyloP100: 8.02
• Publications: 15 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• genetic developmental and epileptic encephalopathy

  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: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_001127644.2
• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA1	NM_001127644.2	MANE Select	c.655G>A	p.Asp219Asn	missense	Exon 7 of 10	NP_001121116.1
	GABRA1	NM_000806.5		c.655G>A	p.Asp219Asn	missense	Exon 8 of 11	NP_000797.2
	GABRA1	NM_001127643.2		c.655G>A	p.Asp219Asn	missense	Exon 8 of 11	NP_001121115.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA1	ENST00000393943.10	TSL:1 MANE Select	c.655G>A	p.Asp219Asn	missense	Exon 7 of 10	ENSP00000377517.4
	GABRA1	ENST00000023897.10	TSL:1	c.655G>A	p.Asp219Asn	missense	Exon 8 of 11	ENSP00000023897.6
	GABRA1	ENST00000428797.7	TSL:1	c.655G>A	p.Asp219Asn	missense	Exon 8 of 11	ENSP00000393097.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: risk factor

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	Epilepsy, idiopathic generalized, susceptibility to, 13 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.016	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		8.0
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.50
Sift	Benign	0.098	T
Sift4G	Benign	0.074	T
Polyphen		1.0	D
Vest4		0.68
MutPred		0.47		Loss of sheet (P = 0.0817)
MVP		0.93
MPC		2.2
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.51
gMVP		0.91
Mutation Taster		=3/97	disease causing

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: rs587777364; hg19: chr5-161309659;