Genetic Variant GNB3:p.Asp254Asp (chr12-6845648-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_StrongBP7BA1

The NM_002075.4(GNB3):c.762C>T(p.Asp254Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00567 in 1,613,990 control chromosomes in the GnomAD database, including 415 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 64 hom., cov: 32)

Exomes 𝑓: 0.0051 ( 351 hom. )

Consequence

GNB3
NM_002075.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.74

Publications

6 publications found

Variant links:

Genes affected

GNB3 (HGNC:4400): (G protein subunit beta 3) Heterotrimeric guanine nucleotide-binding proteins (G proteins), which integrate signals between receptors and effector proteins, are composed of an alpha, a beta, and a gamma subunit. These subunits are encoded by families of related genes. This gene encodes a beta subunit which belongs to the WD repeat G protein beta family. Beta subunits are important regulators of alpha subunits, as well as of certain signal transduction receptors and effectors. A single-nucleotide polymorphism (C825T) in this gene is associated with essential hypertension and obesity. This polymorphism is also associated with the occurrence of the splice variant GNB3-s, which appears to have increased activity. GNB3-s is an example of alternative splicing caused by a nucleotide change outside of the splice donor and acceptor sites. Alternative splicing results in multiple transcript variants. Additional alternatively spliced transcript variants of this gene have been described, but their full-length nature is not known. [provided by RefSeq, Jul 2014]

GNB3 links:

CDCA3 (HGNC:14624): (cell division cycle associated 3) Predicted to be involved in cell division and protein ubiquitination. Located in adherens junction. [provided by Alliance of Genome Resources, Apr 2022]

CDCA3 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=-0.47).

BP6

Variant 12-6845648-C-T is Benign according to our data. Variant chr12-6845648-C-T is described in ClinVar as Benign. ClinVar VariationId is 1169656.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.74 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0668 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002075.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GNB3	NM_002075.4	MANE Select	c.762C>T	p.Asp254Asp	synonymous	Exon 9 of 10	NP_002066.1	P16520-1
GNB3	NM_001297571.2		c.759C>T	p.Asp253Asp	synonymous	Exon 9 of 10	NP_001284500.1	E9PCP0
CDCA3	NM_001297603.3		c.*1140G>A		3_prime_UTR	Exon 5 of 5	NP_001284532.1	F8WDL1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GNB3	ENST00000229264.8	TSL:5 MANE Select	c.762C>T	p.Asp254Asp	synonymous	Exon 9 of 10	ENSP00000229264.3	P16520-1
GNB3	ENST00000435982.6	TSL:1	c.759C>T	p.Asp253Asp	synonymous	Exon 9 of 10	ENSP00000414734.2	E9PCP0
GNB3	ENST00000884021.1		c.762C>T	p.Asp254Asp	synonymous	Exon 8 of 9	ENSP00000554080.1

Frequencies

GnomAD3 genomes

AF:

0.0112

AC:

1703

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00799

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0698

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.0414

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.0186

GnomAD2 exomes

AF:

0.0198

AC:

4976

AN:

251200

AF XY:

0.0151

show subpopulations

Gnomad AFR exome

AF:

0.00800

Gnomad AMR exome

AF:

0.114

Gnomad ASJ exome

AF:

0.000993

Gnomad EAS exome

AF:

0.0369

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000238

Gnomad OTH exome

AF:

0.0143

GnomAD4 exome

AF:

0.00509

AC:

7437

AN:

1461666

Hom.:

351

Cov.:

AF XY:

0.00450

AC XY:

3270

AN XY:

727156

show subpopulations

African (AFR)

AF:

0.00762

AC:

255

AN:

33480

American (AMR)

AF:

0.107

AC:

4791

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00145

AC:

AN:

26134

East Asian (EAS)

AF:

0.0392

AC:

1556

AN:

39700

South Asian (SAS)

AF:

0.00314

AC:

271

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53234

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000155

AC:

172

AN:

1111974

Other (OTH)

AF:

0.00576

AC:

348

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

436

872

1309

1745

2181

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

116

232

348

464

580

<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:

0.0113

AC:

1714

AN:

152324

Hom.:

Cov.:

AF XY:

0.0124

AC XY:

925

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.00806

AC:

335

AN:

41570

American (AMR)

AF:

0.0703

AC:

1076

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.0413

AC:

214

AN:

5182

South Asian (SAS)

AF:

0.00393

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000412

AC:

AN:

68030

Other (OTH)

AF:

0.0184

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

160

239

319

399

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:

0.00316

Hom.:

Bravo

AF:

0.0172

Asia WGS

AF:

0.0190

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000237

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.80

PhyloP100

2.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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.

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