4-46250049-C-G

Variant names:

• chr4-46250049-C-G
• rs573400
• NM_000807.4:c.*259G>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.*259G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GABRA2 NM_000807.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.265
• Publications: 17 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=-0.9).

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.*259G>C		3_prime_UTR	Exon 10 of 10	NP_000798.2
	GABRA2	NM_001330690.2		c.*259G>C		3_prime_UTR	Exon 11 of 11	NP_001317619.1
	GABRA2	NM_001377144.1		c.*259G>C		3_prime_UTR	Exon 11 of 11	NP_001364073.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA2	ENST00000381620.9	TSL:1 MANE Select	c.*259G>C		3_prime_UTR	Exon 10 of 10	ENSP00000371033.4
	GABRA2	ENST00000630416.2	TSL:2	n.*1526G>C		non_coding_transcript_exon	Exon 10 of 10	ENSP00000486333.1
	GABRA2	ENST00000356504.5	TSL:2	c.*259G>C		3_prime_UTR	Exon 9 of 9	ENSP00000348897.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 205842 Hom.: 0 Cov.: 2 AF XY: 0.00 AC XY: 0 AN XY: 106456

African (AFR) AF: 0.00 AC: 0 AN: 6394

American (AMR) AF: 0.00 AC: 0 AN: 7998

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7436

East Asian (EAS) AF: 0.00 AC: 0 AN: 17018

South Asian (SAS) AF: 0.00 AC: 0 AN: 12080

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 11864

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1000

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 128924

Other (OTH) AF: 0.00 AC: 0 AN: 13128

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.056
DANN	Benign	0.53
PhyloP100		-0.27

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: rs573400; hg19: chr4-46252066;