chr12-6845711-C-A

Variant names:

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

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_Moderate

The NM_001297603.3(CDCA3):c.*1077G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Note: NM_001297603.3 is not a MANE Select or MANE Plus Clinical transcript for CDCA3; the reported annotation may differ from that of the MANE-designated reference transcript for this gene. The gene CDCA3 is a known oncogene (CancerMine: 3 oncogene citations). The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. 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 Uncertain Significance (no review stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDCA3 NM_001297603.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.90
• Publications: 0 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 ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001297603.3. 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>A p.Ser275Ser	synonymous	Exon 9 of 10	Prot: NP_002066.1 UniProt:
	GNB3 NM_001297571.2		c.822C>A p.Ser274Ser	synonymous	Exon 9 of 10	Prot: NP_001284500.1 UniProt:
	CDCA3 NM_001297603.3		c.*1077G>T	3_prime_UTR	Exon 5 of 5	Prot: NP_001284532.1 UniProt:

GNB3 NM_002075.4

MANE Select

HGVSc / HGVSpc.825C>Ap.Ser275Ser

Exon rankExon 9 of 10

synonymous

Prot: NP_002066.1UniProt: F1T0G5P16520-1

GNB3 NM_001297571.2

HGVSc / HGVSpc.822C>Ap.Ser274Ser

Exon rankExon 9 of 10

synonymous

Prot: NP_001284500.1UniProt: E9PCP0

CDCA3 NM_001297603.3

HGVSc / HGVSpc.*1077G>T

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>A p.Ser275Ser	synonymous	Exon 9 of 10	Prot: ENSP00000229264.3 UniProt:
	GNB3 ENST00000435982.6	TSL:1	c.822C>A p.Ser274Ser	synonymous	Exon 9 of 10	Prot: ENSP00000414734.2 UniProt:
	GNB3 ENST00000884021.1		c.825C>A p.Ser275Ser	synonymous	Exon 8 of 9	Prot: ENSP00000554080.1 UniProt:

GNB3 ENST00000229264.8

TSL:5MANE Select

HGVSc / HGVSpc.825C>Ap.Ser275Ser

Exon rankExon 9 of 10

synonymous

Prot: ENSP00000229264.3UniProt: P16520-1

GNB3 ENST00000435982.6

TSL:1

HGVSc / HGVSpc.822C>Ap.Ser274Ser

Exon rankExon 9 of 10

synonymous

Prot: ENSP00000414734.2UniProt: E9PCP0

GNB3 ENST00000884021.1

HGVSc / HGVSpc.825C>Ap.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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:35
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	0.0014
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.067
DANN	Benign	0.86
GPN-Star LLR	N/A	-3.6
GPN-Star score	N/A	3.6
PhyloP100	Benign	-4.9

Showing 7 of 7 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.0	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

hg19: chr12-6954875;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar