Genetic Variant NM_002075.4:c.825C>T (chr12-6845711-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.825C>T(p.Ser275Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.337 in 1,613,364 control chromosomes in the GnomAD database, including 100,362 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. S275S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.44 ( 17424 hom., cov: 32)

Exomes 𝑓: 0.33 ( 82938 hom. )

Consequence

GNB3
NM_002075.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: -4.90

Publications

755 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:

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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=-0.68).

BP6

Variant 12-6845711-C-T is Benign according to our data. Variant chr12-6845711-C-T is described in ClinVar as Benign. ClinVar VariationId is 226004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-4.9 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.731 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
GNB3	NM_002075.4	MANE Select	c.825C>T	p.Ser275Ser	synonymous	Exon 9 of 10	NP_002066.1
GNB3	NM_001297571.2		c.822C>T	p.Ser274Ser	synonymous	Exon 9 of 10	NP_001284500.1
CDCA3	NM_001297603.3		c.*1077G>A		3_prime_UTR	Exon 5 of 5	NP_001284532.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GNB3	ENST00000229264.8	TSL:5 MANE Select	c.825C>T	p.Ser275Ser	synonymous	Exon 9 of 10	ENSP00000229264.3
GNB3	ENST00000435982.6	TSL:1	c.822C>T	p.Ser274Ser	synonymous	Exon 9 of 10	ENSP00000414734.2
GNB3	ENST00000884021.1		c.825C>T	p.Ser275Ser	synonymous	Exon 8 of 9	ENSP00000554080.1

Frequencies

GnomAD3 genomes

AF:

0.439

AC:

66665

AN:

151972

Hom.:

17391

Cov.:

show subpopulations

Gnomad AFR

AF:

0.738

Gnomad AMI

AF:

0.344

Gnomad AMR

AF:

0.402

Gnomad ASJ

AF:

0.316

Gnomad EAS

AF:

0.508

Gnomad SAS

AF:

0.315

Gnomad FIN

AF:

0.248

Gnomad MID

AF:

0.497

Gnomad NFE

AF:

0.305

Gnomad OTH

AF:

0.446

GnomAD2 exomes

AF:

0.357

AC:

89686

AN:

251406

AF XY:

0.347

show subpopulations

Gnomad AFR exome

AF:

0.756

Gnomad AMR exome

AF:

0.353

Gnomad ASJ exome

AF:

0.319

Gnomad EAS exome

AF:

0.524

Gnomad FIN exome

AF:

0.255

Gnomad NFE exome

AF:

0.308

Gnomad OTH exome

AF:

0.336

GnomAD4 exome

AF:

0.326

AC:

476344

AN:

1461274

Hom.:

82938

Cov.:

AF XY:

0.325

AC XY:

236257

AN XY:

726988

show subpopulations

African (AFR)

AF:

0.764

AC:

25580

AN:

33466

American (AMR)

AF:

0.356

AC:

15923

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.321

AC:

8386

AN:

26130

East Asian (EAS)

AF:

0.513

AC:

20376

AN:

39688

South Asian (SAS)

AF:

0.321

AC:

27726

AN:

86242

European-Finnish (FIN)

AF:

0.257

AC:

13708

AN:

53384

Middle Eastern (MID)

AF:

0.472

AC:

2720

AN:

5768

European-Non Finnish (NFE)

AF:

0.306

AC:

340232

AN:

1111494

Other (OTH)

AF:

0.359

AC:

21693

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

16935

33870

50804

67739

84674

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11450

22900

34350

45800

57250

<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:

0.439

AC:

66758

AN:

152090

Hom.:

17424

Cov.:

AF XY:

0.434

AC XY:

32272

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.738

AC:

30605

AN:

41498

American (AMR)

AF:

0.402

AC:

6141

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.316

AC:

1096

AN:

3470

East Asian (EAS)

AF:

0.508

AC:

2621

AN:

5158

South Asian (SAS)

AF:

0.316

AC:

1522

AN:

4824

European-Finnish (FIN)

AF:

0.248

AC:

2619

AN:

10576

Middle Eastern (MID)

AF:

0.507

AC:

149

AN:

294

European-Non Finnish (NFE)

AF:

0.305

AC:

20744

AN:

67976

Other (OTH)

AF:

0.450

AC:

948

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1687

3375

5062

6750

8437

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

580

1160

1740

2320

2900

<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:

0.357

Hom.:

43816

Bravo

AF:

0.466

Asia WGS

AF:

0.421

AC:

1461

AN:

3476

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Congenital stationary night blindness 1H (1)

GNB3 POLYMORPHISM (1)

GNB3-related condition (1)

Hypertension, essential, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.22

(source)

DANN

Benign

0.90

PhyloP100

-4.9

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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