rs28551016

Variant names:

• chr15-26940159-C-T
• rs28551016
• NM_000810.4:c.877+82C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000810.4(GABRA5):​c.877+82C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00381 in 1,253,772 control chromosomes in the GnomAD database, including 77 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 0.014 (40 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (37 hom.)
• Consequence: GABRA5 NM_000810.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.30
• Publications: 3 publications found

Genes affected

GABRA5 (HGNC:4079): (gamma-aminobutyric acid type A receptor subunit alpha5) 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. Transcript variants utilizing three different alternative non-coding first exons have been described. [provided by RefSeq, Jul 2008]

GABRA5 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 79

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, 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=-0.9).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0143 (2172/152236) while in subpopulation AFR AF = 0.0459 (1905/41536). AF 95% confidence interval is 0.0441. There are 40 homozygotes in GnomAd4. There are 1013 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2172 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000810.4. 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
	GABRA5	NM_000810.4	MANE Select	c.877+82C>T		intron	N/A	NP_000801.1	P31644
	GABRA5	NM_001165037.2		c.877+82C>T		intron	N/A	NP_001158509.1	P31644

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA5	ENST00000335625.10	TSL:1 MANE Select	c.877+82C>T		intron	N/A	ENSP00000335592.5	P31644
	GABRA5	ENST00000355395.9	TSL:5	c.877+82C>T		intron	N/A	ENSP00000347557.5	P31644
	GABRA5	ENST00000400081.7	TSL:5	c.877+82C>T		intron	N/A	ENSP00000382953.3	P31644

Frequencies

GnomAD3 genomes AF: 0.0142 AC: 2167 AN: 152116 Hom.: 39 Cov.: 32

Gnomad AFR AF: 0.0459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00924

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.0134

GnomAD4 exome AF: 0.00237 AC: 2608 AN: 1101536 Hom.: 37 AF XY: 0.00223 AC XY: 1219 AN XY: 547846

African (AFR) AF: 0.0458 AC: 1187 AN: 25918

American (AMR) AF: 0.00709 AC: 232 AN: 32734

Ashkenazi Jewish (ASJ) AF: 0.00601 AC: 130 AN: 21614

East Asian (EAS) AF: 0.0000294 AC: 1 AN: 34064

South Asian (SAS) AF: 0.000800 AC: 55 AN: 68730

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48264

Middle Eastern (MID) AF: 0.0105 AC: 40 AN: 3802

European-Non Finnish (NFE) AF: 0.000789 AC: 646 AN: 818576

Other (OTH) AF: 0.00663 AC: 317 AN: 47834

GnomAD4 genome AF: 0.0143 AC: 2172 AN: 152236 Hom.: 40 Cov.: 32 AF XY: 0.0136 AC XY: 1013 AN XY: 74442

African (AFR) AF: 0.0459 AC: 1905 AN: 41536

American (AMR) AF: 0.00922 AC: 141 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00692 AC: 24 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.000838 AC: 57 AN: 68026

Other (OTH) AF: 0.0133 AC: 28 AN: 2112

Alfa AF: 0.00647 Hom.: 22

Bravo AF: 0.0166

Asia WGS AF: 0.00606 AC: 23 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.81
DANN	Benign	0.66
PhyloP100		-2.3
Mutation Taster		=100/0	polymorphism

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: rs28551016; hg19: chr15-27185306;