NM_001127644.2:c.1332C>G

Variant names:

• chr5-161897383-C-G
• rs1554087843
• NM_001127644.2:c.1332C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001127644.2(GABRA1):​c.1332C>G​(p.Asn444Lys) variant causes a missense 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GABRA1 NM_001127644.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.847
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA1	NM_001127644.2	MANE Select	c.1332C>G	p.Asn444Lys	missense	Exon 10 of 10	NP_001121116.1	P14867
	GABRA1	NM_000806.5		c.1332C>G	p.Asn444Lys	missense	Exon 11 of 11	NP_000797.2	A8K177
	GABRA1	NM_001127643.2		c.1332C>G	p.Asn444Lys	missense	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.1332C>G	p.Asn444Lys	missense	Exon 10 of 10	ENSP00000377517.4	P14867
	GABRA1	ENST00000023897.10	TSL:1	c.1332C>G	p.Asn444Lys	missense	Exon 11 of 11	ENSP00000023897.6	P14867
	GABRA1	ENST00000428797.7	TSL:1	c.1332C>G	p.Asn444Lys	missense	Exon 11 of 11	ENSP00000393097.2	P14867

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	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	Uncertain	0.41
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		0.85
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.56
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.74
MutPred		0.47		Gain of methylation at N444 (P = 0.0071)
MVP		0.83
MPC		1.2
ClinPred		0.93	D
GERP RS		3.5
Varity_R		0.39
gMVP		0.66
Mutation Taster		=42/58	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: rs1554087843; hg19: chr5-161324389;