rs16859227

Variant names:

• chr4-46248588-C-T
• rs16859227
• NM_000807.4:c.*1720G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_000807.4(GABRA2):​c.*1720G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.199 in 151,176 control chromosomes in the GnomAD database, including 3,315 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 0.20 (3315 hom., cov: 33)
  • Failed GnomAD Quality Control
• Consequence: GABRA2 NM_000807.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.555
• Publications: 4 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.244 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA2	NM_000807.4	MANE Select	c.*1720G>A		3_prime_UTR	Exon 10 of 10	NP_000798.2
	GABRA2	NM_001330690.2		c.*1720G>A		3_prime_UTR	Exon 11 of 11	NP_001317619.1
	GABRA2	NM_001377144.1		c.*1720G>A		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.*1720G>A		3_prime_UTR	Exon 10 of 10	ENSP00000371033.4
	GABRA2	ENST00000510861.5	TSL:5	c.*1720G>A		3_prime_UTR	Exon 10 of 10	ENSP00000421828.1
	GABRA2	ENST00000514090.5	TSL:5	c.*1720G>A		3_prime_UTR	Exon 10 of 10	ENSP00000421300.1

Frequencies

GnomAD3 genomes AF: 0.199 AC: 30072 AN: 151058 Hom.: 3313 Cov.: 33

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.288

Gnomad AMR AF: 0.235

Gnomad ASJ AF: 0.207

Gnomad EAS AF: 0.0594

Gnomad SAS AF: 0.0990

Gnomad FIN AF: 0.164

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.247

Gnomad OTH AF: 0.217

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.199 AC: 30094 AN: 151176 Hom.: 3315 Cov.: 33 AF XY: 0.195 AC XY: 14393 AN XY: 73816

African (AFR) AF: 0.142 AC: 5881 AN: 41400

American (AMR) AF: 0.235 AC: 3550 AN: 15092

Ashkenazi Jewish (ASJ) AF: 0.207 AC: 714 AN: 3444

East Asian (EAS) AF: 0.0592 AC: 301 AN: 5088

South Asian (SAS) AF: 0.0991 AC: 477 AN: 4814

European-Finnish (FIN) AF: 0.164 AC: 1729 AN: 10556

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.247 AC: 16651 AN: 67478

Other (OTH) AF: 0.218 AC: 457 AN: 2098

Alfa AF: 0.237 Hom.: 6824

Bravo AF: 0.206

Asia WGS AF: 0.0880 AC: 306 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	12
DANN	Benign	0.62
PhyloP100		0.56
Mutation Taster		=100/0	polymorphism (auto)

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: rs16859227; hg19: chr4-46250605;