rs279858

Positions:

• chr4-46312576-T-A
• chr4-46312576-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_000807.4(GABRA2):​c.396A>T​(p.Lys132Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GABRA2 NM_000807.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.110

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GABRA2. . Gene score misZ 3.1277 (greater than the threshold 3.09). Trascript score misZ 3.4041 (greater than threshold 3.09). GenCC has associacion of gene with developmental and epileptic encephalopathy, 78, undetermined early-onset epileptic encephalopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.775

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABRA2	NM_000807.4	c.396A>T	p.Lys132Asn	missense_variant	5/10	ENST00000381620.9	NP_000798.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRA2	ENST00000381620.9	c.396A>T	p.Lys132Asn	missense_variant	5/10	1	NM_000807.4	ENSP00000371033	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D;D;D;D;T;T;.;.;.
Eigen	Benign	-0.054
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.69	D
LIST_S2	Pathogenic	0.98	.;.;.;D;D;D;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.78	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Pathogenic	3.3	M;M;M;M;.;.;.;.;.
MutationTaster	Benign	0.00031	P;P;P;P;P;P;P
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-4.3	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;.;.
Polyphen		1.0	D;D;D;D;.;.;D;.;.
Vest4		0.81
MutPred		0.63		Loss of methylation at K132 (P = 0.0083);Loss of methylation at K132 (P = 0.0083);Loss of methylation at K132 (P = 0.0083);Loss of methylation at K132 (P = 0.0083);.;Loss of methylation at K132 (P = 0.0083);Loss of methylation at K132 (P = 0.0083);Loss of methylation at K132 (P = 0.0083);Loss of methylation at K132 (P = 0.0083);
MVP		0.94
MPC		3.0
ClinPred		1.0	D
GERP RS		-6.0
Varity_R		0.88
gMVP		0.96

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

Publications

LitVar

Other links and lift over

dbSNP: rs279858; hg19: chr4-46314593; COSMIC: COSV62917038;