NM_000807.4:c.1288G>T

Variant names:

• chr4-46250376-C-A
• NM_000807.4:c.1288G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000807.4(GABRA2):​c.1288G>T​(p.Gly430Cys) variant causes a missense change. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GABRA2 NM_000807.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.06
• Publications: 0 publications found

Genes affected

GABRA2 (HGNC:4076): (gamma-aminobutyric acid type A receptor subunit alpha2) 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. At least 16 distinct subunits of GABA-A receptors have been identified. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2013]

GABRA2 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 78

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.836

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000807.4. 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
	GABRA2	NM_000807.4	MANE Select	c.1288G>T	p.Gly430Cys	missense	Exon 10 of 10	NP_000798.2	P47869-1
	GABRA2	NM_001330690.2		c.1468G>T	p.Gly490Cys	missense	Exon 11 of 11	NP_001317619.1	E9PBQ7
	GABRA2	NM_001377144.1		c.1468G>T	p.Gly490Cys	missense	Exon 11 of 11	NP_001364073.1	E9PBQ7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA2	ENST00000381620.9	TSL:1 MANE Select	c.1288G>T	p.Gly430Cys	missense	Exon 10 of 10	ENSP00000371033.4	P47869-1
	GABRA2	ENST00000507069.5	TSL:3	c.1468G>T	p.Gly490Cys	missense	Exon 10 of 10	ENSP00000427603.1	E9PBQ7
	GABRA2	ENST00000863565.1		c.1366G>T	p.Gly456Cys	missense	Exon 11 of 11	ENSP00000533624.1

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	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.077	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		6.1
PrimateAI	Pathogenic	0.95	D
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.78
Sift	Benign	0.13	T
Sift4G	Benign	0.077	T
Polyphen		1.0	D
Vest4		0.78
MutPred		0.62		Loss of catalytic residue at P426 (P = 0.0694)
MVP		0.91
MPC		0.90
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.50
gMVP		0.79
Mutation Taster		=20/80	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

hg19: chr4-46252393; COSMIC: COSV62914340;