Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_000814.6(GABRB3):c.1005C>T(p.Gly335Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00246 in 1,614,124 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G335G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0085 ( 24 hom., cov: 33)

Exomes 𝑓: 0.0018 ( 30 hom. )

Consequence

GABRB3
NM_000814.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.973

Publications

4 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.43).

BP6

Variant 15-26561007-G-A is Benign according to our data. Variant chr15-26561007-G-A is described in ClinVar as Benign. ClinVar VariationId is 256817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.973 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00849 (1293/152244) while in subpopulation AFR AF = 0.025 (1038/41546). AF 95% confidence interval is 0.0237. There are 24 homozygotes in GnomAd4. There are 598 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 1293 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.1005C>T	p.Gly335Gly	synonymous	Exon 8 of 9	NP_000805.1
GABRB3	NM_021912.5		c.1005C>T	p.Gly335Gly	synonymous	Exon 8 of 9	NP_068712.1
GABRB3	NM_001191321.3		c.792C>T	p.Gly264Gly	synonymous	Exon 6 of 7	NP_001178250.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GABRB3	ENST00000311550.10	TSL:1 MANE Select	c.1005C>T	p.Gly335Gly	synonymous	Exon 8 of 9	ENSP00000308725.5
GABRB3	ENST00000541819.6	TSL:1	c.1173C>T	p.Gly391Gly	synonymous	Exon 9 of 10	ENSP00000442408.2
GABRB3	ENST00000299267.9	TSL:1	c.1005C>T	p.Gly335Gly	synonymous	Exon 8 of 9	ENSP00000299267.4

Frequencies

GnomAD3 genomes

AF:

0.00847

AC:

1289

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0249

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00720

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00135

Gnomad OTH

AF:

0.0129

GnomAD2 exomes

AF:

0.00350

AC:

881

AN:

251464

AF XY:

0.00322

show subpopulations

Gnomad AFR exome

AF:

0.0282

Gnomad AMR exome

AF:

0.00413

Gnomad ASJ exome

AF:

0.00318

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00144

Gnomad OTH exome

AF:

0.00342

GnomAD4 exome

AF:

0.00184

AC:

2684

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00182

AC XY:

1320

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.0274

AC:

919

AN:

33480

American (AMR)

AF:

0.00443

AC:

198

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00352

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00234

AC:

202

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.0276

AC:

159

AN:

5768

European-Non Finnish (NFE)

AF:

0.000739

AC:

822

AN:

1111998

Other (OTH)

AF:

0.00483

AC:

292

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

175

350

524

699

874

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

168

224

280

<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:

0.00849

AC:

1293

AN:

152244

Hom.:

Cov.:

AF XY:

0.00803

AC XY:

598

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.0250

AC:

1038

AN:

41546

American (AMR)

AF:

0.00719

AC:

110

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3470

East Asian (EAS)

AF:

0.000194

AC:

AN:

5154

South Asian (SAS)

AF:

0.00269

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00134

AC:

AN:

68026

Other (OTH)

AF:

0.0128

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

136

204

272

340

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00399

Hom.:

Bravo

AF:

0.0104

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00284

EpiControl

AF:

0.00273

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

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

Seizure (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

8.3

(source)

DANN

Benign

0.67

PhyloP100

0.97

Mutation Taster

=89/11

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs74907974

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over