Genetic Variant NM_000814.6:c.545-678G>C (chr15-26581134-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000814.6(GABRB3):c.545-678G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.895 in 161,088 control chromosomes in the GnomAD database, including 66,142 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 0.89 ( 61867 hom., cov: 31)

Exomes 𝑓: 0.98 ( 4275 hom. )

Consequence

GABRB3
NM_000814.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.12

Publications

2 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:

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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=-0.97).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.979 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRB3	NM_000814.6 link	c.545-678G>C		intron_variant	Intron 5 of 8	ENST00000311550.10	NP_000805.1	P28472-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRB3	ENST00000311550.10 link	c.545-678G>C		intron_variant	Intron 5 of 8	1	NM_000814.6	ENSP00000308725.5		P28472-1

Frequencies

GnomAD3 genomes

AF:

0.891

AC:

135413

AN:

152040

Hom.:

61837

Cov.:

show subpopulations

Gnomad AFR

AF:

0.661

Gnomad AMI

AF:

0.999

Gnomad AMR

AF:

0.945

Gnomad ASJ

AF:

0.940

Gnomad EAS

AF:

0.964

Gnomad SAS

AF:

0.984

Gnomad FIN

AF:

0.995

Gnomad MID

AF:

0.908

Gnomad NFE

AF:

0.985

Gnomad OTH

AF:

0.917

GnomAD4 exome

AF:

0.977

AC:

8729

AN:

8930

Hom.:

4275

Cov.:

AF XY:

0.979

AC XY:

4564

AN XY:

4664

show subpopulations

African (AFR)

AF:

0.482

AC:

AN:

American (AMR)

AF:

0.964

AC:

2272

AN:

2356

Ashkenazi Jewish (ASJ)

AF:

0.938

AC:

AN:

East Asian (EAS)

AF:

0.966

AC:

545

AN:

564

South Asian (SAS)

AF:

0.995

AC:

1104

AN:

1110

European-Finnish (FIN)

AF:

0.963

AC:

AN:

Middle Eastern (MID)

AF:

1.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.989

AC:

4397

AN:

4444

Other (OTH)

AF:

0.963

AC:

283

AN:

294

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

204

306

408

510

<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:

0.890

AC:

135489

AN:

152158

Hom.:

61867

Cov.:

AF XY:

0.894

AC XY:

66556

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.660

AC:

27371

AN:

41442

American (AMR)

AF:

0.945

AC:

14456

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.940

AC:

3265

AN:

3472

East Asian (EAS)

AF:

0.964

AC:

4967

AN:

5154

South Asian (SAS)

AF:

0.985

AC:

4746

AN:

4820

European-Finnish (FIN)

AF:

0.995

AC:

10563

AN:

10620

Middle Eastern (MID)

AF:

0.912

AC:

268

AN:

294

European-Non Finnish (NFE)

AF:

0.985

AC:

67006

AN:

68038

Other (OTH)

AF:

0.918

AC:

1936

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

610

1220

1831

2441

3051

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

890

1780

2670

3560

4450

<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:

0.939

Hom.:

3386

Bravo

AF:

0.875

Asia WGS

AF:

0.942

AC:

3277

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.97

CADD

Benign

0.018

(source)

DANN

Benign

0.39

PhyloP100

-1.1

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over