12-6845711-C-T

Variant names:

• chr12-6845711-C-T
• rs5443
• NM_002075.4:c.825C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: -4.90
• Publications: 755 publications found

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]

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]

ACMG classification

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	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.: 32

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

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.: 35 AF XY: 0.325 AC XY: 236257 AN XY: 726988

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

GnomAD4 genome AF: 0.439 AC: 66758 AN: 152090 Hom.: 17424 Cov.: 32 AF XY: 0.434 AC XY: 32272 AN XY: 74342

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

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

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Congenital stationary night blindness 1H (1)
-	-	1	GNB3 POLYMORPHISM (1)
-	-	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
DANN	Benign	0.90
PhyloP100		-4.9
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs5443; hg19: chr12-6954875; COSMIC: COSV57528272; COSMIC: COSV57528272;