Genetic Variant NM_000812.4:c.846A>G (chr4-47406692-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000812.4(GABRB1):c.846A>G(p.Thr282Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.297 in 1,613,724 control chromosomes in the GnomAD database, including 74,786 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. T282T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.28 ( 6283 hom., cov: 32)

Exomes 𝑓: 0.30 ( 68503 hom. )

Consequence

GABRB1
NM_000812.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.03

Publications

22 publications found

Variant links:

Genes affected

GABRB1 (HGNC:4081): (gamma-aminobutyric acid type A receptor subunit beta1) The gamma-aminobutyric acid (GABA) A receptor is a multisubunit chloride channel that mediates the fastest inhibitory synaptic transmission in the central nervous system. This gene encodes GABA A receptor, beta 1 subunit. It is mapped to chromosome 4p12 in a cluster comprised of genes encoding alpha 4, alpha 2 and gamma 1 subunits of the GABA A receptor. Alteration of this gene is implicated in the pathogenetics of schizophrenia. [provided by RefSeq, Jul 2008]

GABRB1 Gene-Disease associations (from GenCC):

developmental and epileptic encephalopathy, 45
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
genetic developmental and epileptic encephalopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

GABRB1 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=-0.92).

BP6

Variant 4-47406692-A-G is Benign according to our data. Variant chr4-47406692-A-G is described in ClinVar as Benign. ClinVar VariationId is 1280390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.03 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.315 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000812.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRB1	NM_000812.4	MANE Select	c.846A>G	p.Thr282Thr	synonymous	Exon 8 of 9	NP_000803.2	X5DNL6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRB1	ENST00000295454.8	TSL:1 MANE Select	c.846A>G	p.Thr282Thr	synonymous	Exon 8 of 9	ENSP00000295454.3	P18505-1

Frequencies

GnomAD3 genomes

AF:

0.278

AC:

42252

AN:

151994

Hom.:

6277

Cov.:

show subpopulations

Gnomad AFR

AF:

0.268

Gnomad AMI

AF:

0.237

Gnomad AMR

AF:

0.221

Gnomad ASJ

AF:

0.334

Gnomad EAS

AF:

0.0154

Gnomad SAS

AF:

0.203

Gnomad FIN

AF:

0.286

Gnomad MID

AF:

0.369

Gnomad NFE

AF:

0.318

Gnomad OTH

AF:

0.280

GnomAD2 exomes

AF:

0.255

AC:

64042

AN:

251168

AF XY:

0.261

show subpopulations

Gnomad AFR exome

AF:

0.272

Gnomad AMR exome

AF:

0.153

Gnomad ASJ exome

AF:

0.334

Gnomad EAS exome

AF:

0.00810

Gnomad FIN exome

AF:

0.273

Gnomad NFE exome

AF:

0.326

Gnomad OTH exome

AF:

0.287

GnomAD4 exome

AF:

0.299

AC:

436528

AN:

1461612

Hom.:

68503

Cov.:

AF XY:

0.297

AC XY:

216055

AN XY:

727110

show subpopulations

African (AFR)

AF:

0.276

AC:

9240

AN:

33478

American (AMR)

AF:

0.162

AC:

7266

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.338

AC:

8832

AN:

26132

East Asian (EAS)

AF:

0.0255

AC:

1014

AN:

39698

South Asian (SAS)

AF:

0.209

AC:

18041

AN:

86248

European-Finnish (FIN)

AF:

0.270

AC:

14432

AN:

53418

Middle Eastern (MID)

AF:

0.388

AC:

2238

AN:

5764

European-Non Finnish (NFE)

AF:

0.322

AC:

358054

AN:

1111766

Other (OTH)

AF:

0.288

AC:

17411

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

15608

31216

46825

62433

78041

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11370

22740

34110

45480

56850

<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:

0.278

AC:

42284

AN:

152112

Hom.:

6283

Cov.:

AF XY:

0.273

AC XY:

20325

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.268

AC:

11111

AN:

41488

American (AMR)

AF:

0.220

AC:

3369

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.334

AC:

1159

AN:

3472

East Asian (EAS)

AF:

0.0154

AC:

AN:

5186

South Asian (SAS)

AF:

0.203

AC:

978

AN:

4810

European-Finnish (FIN)

AF:

0.286

AC:

3021

AN:

10574

Middle Eastern (MID)

AF:

0.379

AC:

110

AN:

290

European-Non Finnish (NFE)

AF:

0.318

AC:

21645

AN:

67982

Other (OTH)

AF:

0.282

AC:

595

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1540

3080

4621

6161

7701

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

436

872

1308

1744

2180

<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:

0.305

Hom.:

17163

Bravo

AF:

0.274

Asia WGS

AF:

0.128

AC:

445

AN:

3478

EpiCase

AF:

0.337

EpiControl

AF:

0.338

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Developmental and epileptic encephalopathy, 45 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.012

(source)

DANN

Benign

0.29

PhyloP100

-2.0

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