12-6845700-G-A

Variant names:

• chr12-6845700-G-A
• rs5442
• NM_002075.4:c.814G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002075.4(GNB3):​c.814G>A​(p.Gly272Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0593 in 1,613,922 control chromosomes in the GnomAD database, including 3,298 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (208 hom., cov: 32)
  • Exomes 𝑓: 0.061 (3090 hom.)
• Consequence: GNB3 NM_002075.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 10.0
• Publications: 59 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004829645).
• BP6: Variant 12-6845700-G-A is Benign according to our data. Variant chr12-6845700-G-A is described in ClinVar as Benign. ClinVar VariationId is 1170122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0641 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.814G>A	p.Gly272Ser	missense	Exon 9 of 10	NP_002066.1
	GNB3	NM_001297571.2		c.811G>A	p.Gly271Ser	missense	Exon 9 of 10	NP_001284500.1
	CDCA3	NM_001297603.3		c.*1088C>T		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.814G>A	p.Gly272Ser	missense	Exon 9 of 10	ENSP00000229264.3
	GNB3	ENST00000435982.6	TSL:1	c.811G>A	p.Gly271Ser	missense	Exon 9 of 10	ENSP00000414734.2
	GNB3	ENST00000537035.1	TSL:5	c.691G>A	p.Gly231Ser	missense	Exon 8 of 8	ENSP00000445967.1

Frequencies

GnomAD3 genomes AF: 0.0452 AC: 6873 AN: 152150 Hom.: 209 Cov.: 32

Gnomad AFR AF: 0.0116

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0418

Gnomad ASJ AF: 0.0720

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00909

Gnomad FIN AF: 0.0802

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0657

Gnomad OTH AF: 0.0455

GnomAD2 exomes AF: 0.0484 AC: 12177 AN: 251402 AF XY: 0.0488

Gnomad AFR exome AF: 0.0104

Gnomad AMR exome AF: 0.0266

Gnomad ASJ exome AF: 0.0696

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.0792

Gnomad NFE exome AF: 0.0695

Gnomad OTH exome AF: 0.0577

GnomAD4 exome AF: 0.0608 AC: 88879 AN: 1461654 Hom.: 3090 Cov.: 32 AF XY: 0.0596 AC XY: 43335 AN XY: 727134

African (AFR) AF: 0.00851 AC: 285 AN: 33478

American (AMR) AF: 0.0277 AC: 1237 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0702 AC: 1836 AN: 26136

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39700

South Asian (SAS) AF: 0.0148 AC: 1275 AN: 86258

European-Finnish (FIN) AF: 0.0798 AC: 4262 AN: 53382

Middle Eastern (MID) AF: 0.0468 AC: 270 AN: 5768

European-Non Finnish (NFE) AF: 0.0686 AC: 76273 AN: 1111816

Other (OTH) AF: 0.0569 AC: 3435 AN: 60392

GnomAD4 genome AF: 0.0451 AC: 6868 AN: 152268 Hom.: 208 Cov.: 32 AF XY: 0.0441 AC XY: 3283 AN XY: 74456

African (AFR) AF: 0.0116 AC: 483 AN: 41544

American (AMR) AF: 0.0417 AC: 638 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0720 AC: 249 AN: 3460

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00890 AC: 43 AN: 4834

European-Finnish (FIN) AF: 0.0802 AC: 851 AN: 10610

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0657 AC: 4472 AN: 68018

Other (OTH) AF: 0.0445 AC: 94 AN: 2112

Alfa AF: 0.0578 Hom.: 1218

Bravo AF: 0.0420

TwinsUK AF: 0.0618 AC: 229

ALSPAC AF: 0.0651 AC: 251

ESP6500AA AF: 0.0136 AC: 60

ESP6500EA AF: 0.0681 AC: 586

ExAC AF: 0.0499 AC: 6059

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.0665

EpiControl AF: 0.0702

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 21675276)

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0048	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		10
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.097	T
Polyphen		0.97	D
Vest4		0.30
MPC		0.85
ClinPred		0.032	T
GERP RS		4.6
Varity_R		0.90
gMVP		0.69
Mutation Taster		=83/17	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs5442; hg19: chr12-6954864; COSMIC: COSV57528327; COSMIC: COSV57528327;