dbSNP rs76812964: GABRB3:p.Ser261Ser (chr15-26567633-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000814.6(GABRB3):c.783G>A(p.Ser261Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0297 in 1,613,916 control chromosomes in the GnomAD database, including 854 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 52 hom., cov: 33)

Exomes 𝑓: 0.030 ( 802 hom. )

Consequence

GABRB3
NM_000814.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.47

Publications

6 publications found

Variant links:

Genes affected

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

GABRB3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 15-26567633-C-T is Benign according to our data. Variant chr15-26567633-C-T is described in ClinVar as Benign. ClinVar VariationId is 256821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.47 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0225 (3430/152242) while in subpopulation NFE AF = 0.0325 (2210/68016). AF 95% confidence interval is 0.0314. There are 52 homozygotes in GnomAd4. There are 1626 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 3430 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000814.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GABRB3	NM_000814.6	MANE Select	c.783G>A	p.Ser261Ser	synonymous	Exon 7 of 9	NP_000805.1
GABRB3	NM_021912.5		c.783G>A	p.Ser261Ser	synonymous	Exon 7 of 9	NP_068712.1
GABRB3	NM_001191321.3		c.570G>A	p.Ser190Ser	synonymous	Exon 5 of 7	NP_001178250.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GABRB3	ENST00000311550.10	TSL:1 MANE Select	c.783G>A	p.Ser261Ser	synonymous	Exon 7 of 9	ENSP00000308725.5
GABRB3	ENST00000541819.6	TSL:1	c.951G>A	p.Ser317Ser	synonymous	Exon 8 of 10	ENSP00000442408.2
GABRB3	ENST00000299267.9	TSL:1	c.783G>A	p.Ser261Ser	synonymous	Exon 7 of 9	ENSP00000299267.4

Frequencies

GnomAD3 genomes

AF:

0.0225

AC:

3427

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00577

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0217

Gnomad ASJ

AF:

0.0447

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00435

Gnomad FIN

AF:

0.0387

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0325

Gnomad OTH

AF:

0.0259

GnomAD2 exomes

AF:

0.0247

AC:

6219

AN:

251310

AF XY:

0.0249

show subpopulations

Gnomad AFR exome

AF:

0.00591

Gnomad AMR exome

AF:

0.0174

Gnomad ASJ exome

AF:

0.0457

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0367

Gnomad NFE exome

AF:

0.0342

Gnomad OTH exome

AF:

0.0253

GnomAD4 exome

AF:

0.0305

AC:

44525

AN:

1461674

Hom.:

802

Cov.:

AF XY:

0.0297

AC XY:

21609

AN XY:

727136

show subpopulations

African (AFR)

AF:

0.00469

AC:

157

AN:

33480

American (AMR)

AF:

0.0181

AC:

811

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0470

AC:

1228

AN:

26134

East Asian (EAS)

AF:

0.000126

AC:

AN:

39698

South Asian (SAS)

AF:

0.00670

AC:

578

AN:

86258

European-Finnish (FIN)

AF:

0.0354

AC:

1890

AN:

53338

Middle Eastern (MID)

AF:

0.0125

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0344

AC:

38264

AN:

1111888

Other (OTH)

AF:

0.0252

AC:

1520

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

2140

4280

6419

8559

10699

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1416

2832

4248

5664

7080

<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:

0.0225

AC:

3430

AN:

152242

Hom.:

Cov.:

AF XY:

0.0218

AC XY:

1626

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.00575

AC:

239

AN:

41552

American (AMR)

AF:

0.0217

AC:

332

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0447

AC:

155

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5172

South Asian (SAS)

AF:

0.00435

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0387

AC:

410

AN:

10602

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0325

AC:

2210

AN:

68016

Other (OTH)

AF:

0.0270

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

179

357

536

714

893

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.0301

Hom.:

Bravo

AF:

0.0213

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.0320

EpiControl

AF:

0.0334

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Epilepsy, childhood absence, susceptibility to, 1;C2677087:Epilepsy, childhood absence, susceptibility to, 5 (1)

not provided (1)

Seizure (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.54

(source)

DANN

Benign

0.43

PhyloP100

-1.5

Mutation Taster

=98/2

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over