4-46332793-A-G

Variant names:

• chr4-46332793-A-G
• rs279828
• NM_000807.4:c.188-111T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000807.4(GABRA2):​c.188-111T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000227 in 440,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: GABRA2 NM_000807.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.105
• 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, Labcorp Genetics (formerly Invitae), G2P
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA2	NM_000807.4	MANE Select	c.188-111T>C		intron	N/A	NP_000798.2
	GABRA2	NM_001330690.2		c.188-111T>C		intron	N/A	NP_001317619.1
	GABRA2	NM_001377144.1		c.188-111T>C		intron	N/A	NP_001364073.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA2	ENST00000381620.9	TSL:1 MANE Select	c.188-111T>C		intron	N/A	ENSP00000371033.4
	GABRA2	ENST00000515082.5	TSL:1	c.188-111T>C		intron	N/A	ENSP00000423840.1
	GABRA2	ENST00000507069.5	TSL:3	c.188-111T>C		intron	N/A	ENSP00000427603.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000227 AC: 1 AN: 440852 Hom.: 0 AF XY: 0.00000425 AC XY: 1 AN XY: 235272

African (AFR) AF: 0.00 AC: 0 AN: 10942

American (AMR) AF: 0.00 AC: 0 AN: 18664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13630

East Asian (EAS) AF: 0.00 AC: 0 AN: 28452

South Asian (SAS) AF: 0.0000285 AC: 1 AN: 35088

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42670

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1850

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 265660

Other (OTH) AF: 0.00 AC: 0 AN: 23896

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.0
DANN	Benign	0.24
PhyloP100		-0.10

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: rs279828; hg19: chr4-46334810;