4-46354935-C-T

Variant names:

• chr4-46354935-C-T
• rs1442059
• NM_000807.4:c.188-22253G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000807.4(GABRA2):​c.188-22253G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.575 in 151,950 control chromosomes in the GnomAD database, including 25,362 homozygotes. 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: 𝑓 0.58 (25362 hom., cov: 32)
• Consequence: GABRA2 NM_000807.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.684
• Publications: 3 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.699 is higher than 0.05.

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.188-22253G>A		intron	N/A	NP_000798.2	P47869-1
	GABRA2	NM_001330690.2		c.188-22253G>A		intron	N/A	NP_001317619.1	E9PBQ7
	GABRA2	NM_001377144.1		c.188-22253G>A		intron	N/A	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.188-22253G>A		intron	N/A	ENSP00000371033.4	P47869-1
	GABRA2	ENST00000515082.5	TSL:1	c.188-22253G>A		intron	N/A	ENSP00000423840.1	G5E9Z6
	GABRA2	ENST00000507069.5	TSL:3	c.188-22253G>A		intron	N/A	ENSP00000427603.1	E9PBQ7

Frequencies

GnomAD3 genomes AF: 0.575 AC: 87315 AN: 151832 Hom.: 25338 Cov.: 32

Gnomad AFR AF: 0.596

Gnomad AMI AF: 0.617

Gnomad AMR AF: 0.527

Gnomad ASJ AF: 0.699

Gnomad EAS AF: 0.429

Gnomad SAS AF: 0.719

Gnomad FIN AF: 0.581

Gnomad MID AF: 0.671

Gnomad NFE AF: 0.565

Gnomad OTH AF: 0.591

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.575 AC: 87380 AN: 151950 Hom.: 25362 Cov.: 32 AF XY: 0.575 AC XY: 42668 AN XY: 74232

African (AFR) AF: 0.596 AC: 24713 AN: 41458

American (AMR) AF: 0.527 AC: 8035 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.699 AC: 2425 AN: 3470

East Asian (EAS) AF: 0.429 AC: 2211 AN: 5156

South Asian (SAS) AF: 0.719 AC: 3462 AN: 4814

European-Finnish (FIN) AF: 0.581 AC: 6122 AN: 10540

Middle Eastern (MID) AF: 0.653 AC: 192 AN: 294

European-Non Finnish (NFE) AF: 0.565 AC: 38410 AN: 67960

Other (OTH) AF: 0.593 AC: 1247 AN: 2104

Alfa AF: 0.391 Hom.: 680

Bravo AF: 0.608

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.3
DANN	Benign	0.51
PhyloP100		-0.68
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1442059; hg19: chr4-46356952;