15-26869757-T-C

Variant names:

• chr15-26869757-T-C
• rs2075716
• NM_000810.4:c.86+423T>C

Variant summary

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

The NM_000810.4(GABRA5):​c.86+423T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.7 in 152,154 control chromosomes in the GnomAD database, including 38,348 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 0.70 (38348 hom., cov: 33)
• Consequence: GABRA5 NM_000810.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.72
• Publications: 6 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]

GABRB3 (HGNC:4083): (gamma-aminobutyric acid type A receptor subunit beta3) This gene encodes a member of the ligand-gated ionic channel family. The encoded protein is one the subunits of a multi-subunit chloride channel that serves as the receptor for gamma-aminobutyric acid, a major inhibitory neurotransmitter of the mammalian nervous system. This gene is located on the long arm of chromosome 15 in a cluster with two other genes encoding related subunits of the family. This gene may be associated with the pathogenesis of several disorders including Angelman syndrome, Prader-Willi syndrome, nonsyndromic orofacial clefts, epilepsy and autism. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Jul 2013]

GABRB3 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 43

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• epilepsy, childhood absence, susceptibility to, 5

  Inheritance: AD, Unknown Classification: DEFINITIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• childhood absence epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Lennox-Gastaut syndrome

  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).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.867 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA5	NM_000810.4	MANE Select	c.86+423T>C		intron	N/A	NP_000801.1
	GABRA5	NM_001165037.2		c.86+423T>C		intron	N/A	NP_001158509.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA5	ENST00000335625.10	TSL:1 MANE Select	c.86+423T>C		intron	N/A	ENSP00000335592.5
	GABRB3	ENST00000541819.6	TSL:1	c.201-53343A>G		intron	N/A	ENSP00000442408.2
	GABRA5	ENST00000355395.9	TSL:5	c.86+423T>C		intron	N/A	ENSP00000347557.5

Frequencies

GnomAD3 genomes AF: 0.700 AC: 106390 AN: 152036 Hom.: 38297 Cov.: 33

Gnomad AFR AF: 0.875

Gnomad AMI AF: 0.633

Gnomad AMR AF: 0.687

Gnomad ASJ AF: 0.585

Gnomad EAS AF: 0.743

Gnomad SAS AF: 0.524

Gnomad FIN AF: 0.628

Gnomad MID AF: 0.595

Gnomad NFE AF: 0.624

Gnomad OTH AF: 0.697

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

GnomAD4 genome AF: 0.700 AC: 106497 AN: 152154 Hom.: 38348 Cov.: 33 AF XY: 0.699 AC XY: 51962 AN XY: 74378

African (AFR) AF: 0.875 AC: 36342 AN: 41548

American (AMR) AF: 0.687 AC: 10494 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.585 AC: 2031 AN: 3470

East Asian (EAS) AF: 0.743 AC: 3836 AN: 5160

South Asian (SAS) AF: 0.524 AC: 2522 AN: 4814

European-Finnish (FIN) AF: 0.628 AC: 6641 AN: 10578

Middle Eastern (MID) AF: 0.612 AC: 180 AN: 294

European-Non Finnish (NFE) AF: 0.624 AC: 42403 AN: 67984

Other (OTH) AF: 0.697 AC: 1471 AN: 2110

Alfa AF: 0.652 Hom.: 44282

Bravo AF: 0.714

Asia WGS AF: 0.676 AC: 2351 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	0.33
DANN	Benign	0.40
PhyloP100		-1.7
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: rs2075716; hg19: chr15-27114904;