chr12-6845711-C-T

Variant names:

• chr12-6845711-C-T
• rs5443
• NM_002075.4:c.825C>T
• GNB3 p.Ser275Ser

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -17 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_StrongBP6_StrongBP7

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 cumulative frequency of 0.337 (AC=543,102) in the gnomAD database across 1,613,364 control chromosomes, including 100,362 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.757. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★).

• 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: 2 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]

GNB3 Gene-Disease associations (from GenCC):

• congenital stationary night blindness 1H

  Inheritance: AR, Unknown Classification: STRONG, LIMITED Submitted by: PanelApp Australia, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• congenital stationary night blindness

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

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, Jul 2025]

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -17 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BP6Reputable source reports benign		ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).
	BP7Synonymous variant, no splicing impact		Synonymous variant at non-conserved position with no predicted splicing impact (BP7); Synonymous at non-conserved position, no splicing concern — benign (BP7).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.7565 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	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	Prot: NP_002066.1 UniProt:
	GNB3 NM_001297571.2		c.822C>T p.Ser274Ser	synonymous	Exon 9 of 10	Prot: NP_001284500.1 UniProt:
	CDCA3 NM_001297603.3		c.*1077G>A	3_prime_UTR	Exon 5 of 5	Prot: NP_001284532.1 UniProt:

GNB3 NM_002075.4

MANE Select

HGVSc / HGVSpc.825C>Tp.Ser275Ser

Exon rankExon 9 of 10

synonymous

Prot: NP_002066.1UniProt: F1T0G5P16520-1

GNB3 NM_001297571.2

HGVSc / HGVSpc.822C>Tp.Ser274Ser

Exon rankExon 9 of 10

synonymous

Prot: NP_001284500.1UniProt: E9PCP0

CDCA3 NM_001297603.3

HGVSc / HGVSpc.*1077G>A

Exon rankExon 5 of 5

3_prime_UTR

Prot: NP_001284532.1UniProt: F8WDL1

Ensembl Transcripts

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

GNB3 ENST00000229264.8

TSL:5MANE Select

HGVSc / HGVSpc.825C>Tp.Ser275Ser

Exon rankExon 9 of 10

synonymous

Prot: ENSP00000229264.3UniProt: P16520-1

GNB3 ENST00000435982.6

TSL:1

HGVSc / HGVSpc.822C>Tp.Ser274Ser

Exon rankExon 9 of 10

synonymous

Prot: ENSP00000414734.2UniProt: E9PCP0

GNB3 ENST00000884021.1

HGVSc / HGVSpc.825C>Tp.Ser275Ser

Exon rankExon 8 of 9

synonymous

Prot: ENSP00000554080.1UniProt: P16520-1

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.439	AC:66665	Hom:17391	AN:151972	Cov:32
GnomAD2 exomes	AF: 0.357	AC:89686	Hom:	AN:251406	Cov:
GnomAD4 exome	AF: 0.326	AC:476344	Hom:82938	AN:1461274	Cov:35
GnomAD4 genome	AF: 0.439	AC:66758	Hom:17424	AN:152090	Cov:32
TOPMed (Bravo)	AF: 0.466	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.363	AC:231037	Hom:47691	AN:636106	Cov:
Local & regional cohorts 11 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.439	AC:1028	Hom:243	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.490	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.327	AC:98	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.450	AC:5850	Hom:	AN:13006	Cov:
GenomeAsia100K	AF: 0.421	AC:1461	Hom:	AN:3476	Cov:
Korea4K (4,157 Koreans)	AF: 0.499	AC:3613	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.526	AC:1058	Hom:	AN:2010	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.500	AC:61292	Hom:15306	AN:122600	Cov:
Turkish Variome	AF: 0.382	AC:2565	Hom:504	AN:6714	Cov:
UK10K	AF: 0.291	AC:2200	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.497	AC:4452	Hom:1107	AN:8960	Cov:

Showing 17 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.315 *	3029	9604	0.312 *	3252	10412
BipEx(Bipolar disorder (including schizoaffective))	0.305	8666	28420	0.291	8384	28844
Epi25(Epilepsy)	0.364	15253	41958	0.359	24029	66888
SCHEMA(Schizophrenia)	0.458	71296	155750	0.453	116317	256712

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

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

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	0.0014
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.22
DANN	Benign	0.90
GPN-Star LLR	N/A	-1.1
GPN-Star score	N/A	1.1
Mutation Taster	N/A	99/1	polymorphism (auto)
PhyloP100	Benign	-4.9

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.070	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs5443;

hg19: chr12-6954875;

COSMIC: COSV57528272;

COSMIC: COSV57528272;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar