dbSNP rs28551016: GABRA5:c.877+82C>T (chr15-26940159-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.30

Publications

3 publications found

Variant links:

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

GABRA5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRA5	NM_000810.4 link	c.877+82C>T		intron_variant	Intron 9 of 10	ENST00000335625.10	NP_000801.1	P31644

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
GABRA5	ENST00000335625.10 link	c.877+82C>T	intron_variant	Intron 9 of 10	1	NM_000810.4	ENSP00000335592.5	P31644
GABRA5	ENST00000355395.9 link	c.877+82C>T	intron_variant	Intron 8 of 9	5		ENSP00000347557.5	P31644
GABRA5	ENST00000400081.7 link	c.877+82C>T	intron_variant	Intron 9 of 10	5		ENSP00000382953.3	P31644

Frequencies

GnomAD3 genomes

AF:

0.0142

AC:

2167

AN:

152116

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00223

AC XY:

1219

AN XY:

547846

show subpopulations

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:

AN:

34064

South Asian (SAS)

AF:

0.000800

AC:

AN:

68730

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48264

Middle Eastern (MID)

AF:

0.0105

AC:

AN:

3802

European-Non Finnish (NFE)

AF:

0.000789

AC:

646

AN:

818576

Other (OTH)

AF:

0.00663

AC:

317

AN:

47834

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

131

263

394

526

657

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

116

174

232

290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0143

AC:

2172

AN:

152236

Hom.:

Cov.:

AF XY:

0.0136

AC XY:

1013

AN XY:

74442

show subpopulations

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:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00166

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000838

AC:

AN:

68026

Other (OTH)

AF:

0.0133

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

104

208

311

415

519

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00647

Hom.:

Bravo

AF:

0.0166

Asia WGS

AF:

0.00606

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.81

(source)

DANN

Benign

0.66

PhyloP100

-2.3

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over