rs1051130

Positions:

• chr6-41936044-A-C
• chr6-41936044-A-G
• chr6-41936044-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001760.5(CCND3):​c.775T>G​(p.Ser259Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.556 in 1,612,694 control chromosomes in the GnomAD database, including 253,044 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.62 (29837 hom., cov: 32)
  • Exomes 𝑓: 0.55 (223207 hom.)
• Consequence: CCND3 NM_001760.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.143

Genes affected

CCND3 (HGNC:1585): (cyclin D3) The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protein abundance through the cell cycle. Cyclins function as regulators of CDK kinases. Different cyclins exhibit distinct expression and degradation patterns which contribute to the temporal coordination of each mitotic event. This cyclin forms a complex with and functions as a regulatory subunit of CDK4 or CDK6, whose activtiy is required for cell cycle G1/S transition. This protein has been shown to interact with and be involved in the phosphorylation of tumor suppressor protein Rb. The CDK4 activity associated with this cyclin was reported to be necessary for cell cycle progression through G2 phase into mitosis after UV radiation. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2008]

CCND3 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.648597E-7).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.798 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCND3	NM_001760.5	c.775T>G	p.Ser259Ala	missense_variant	5/5	ENST00000372991.9	NP_001751.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCND3	ENST00000372991.9	c.775T>G	p.Ser259Ala	missense_variant	5/5	1	NM_001760.5	ENSP00000362082.5

Frequencies

GnomAD3 genomes AF: 0.615 AC: 93438 AN: 151858 Hom.: 29794 Cov.: 32

Gnomad AFR AF: 0.805

Gnomad AMI AF: 0.519

Gnomad AMR AF: 0.541

Gnomad ASJ AF: 0.558

Gnomad EAS AF: 0.523

Gnomad SAS AF: 0.457

Gnomad FIN AF: 0.546

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.551

Gnomad OTH AF: 0.598

GnomAD3 exomes AF: 0.538 AC: 134150 AN: 249276 Hom.: 36941 AF XY: 0.532 AC XY: 71666 AN XY: 134790

Gnomad AFR exome AF: 0.807

Gnomad AMR exome AF: 0.460

Gnomad ASJ exome AF: 0.561

Gnomad EAS exome AF: 0.531

Gnomad SAS exome AF: 0.451

Gnomad FIN exome AF: 0.546

Gnomad NFE exome AF: 0.545

Gnomad OTH exome AF: 0.534

GnomAD4 exome AF: 0.550 AC: 803081 AN: 1460718 Hom.: 223207 Cov.: 48 AF XY: 0.546 AC XY: 396878 AN XY: 726666

Gnomad4 AFR exome AF: 0.808

Gnomad4 AMR exome AF: 0.471

Gnomad4 ASJ exome AF: 0.562

Gnomad4 EAS exome AF: 0.495

Gnomad4 SAS exome AF: 0.450

Gnomad4 FIN exome AF: 0.545

Gnomad4 NFE exome AF: 0.555

Gnomad4 OTH exome AF: 0.561

GnomAD4 genome AF: 0.615 AC: 93523 AN: 151976 Hom.: 29837 Cov.: 32 AF XY: 0.612 AC XY: 45436 AN XY: 74252

Gnomad4 AFR AF: 0.805

Gnomad4 AMR AF: 0.540

Gnomad4 ASJ AF: 0.558

Gnomad4 EAS AF: 0.523

Gnomad4 SAS AF: 0.456

Gnomad4 FIN AF: 0.546

Gnomad4 NFE AF: 0.551

Gnomad4 OTH AF: 0.597

Alfa AF: 0.555 Hom.: 8990

Bravo AF: 0.623

TwinsUK AF: 0.550 AC: 2041

ALSPAC AF: 0.554 AC: 2135

ESP6500AA AF: 0.776 AC: 3420

ESP6500EA AF: 0.547 AC: 4700

ExAC AF: 0.541 AC: 65706

Asia WGS AF: 0.514 AC: 1785 AN: 3478

EpiCase AF: 0.538

EpiControl AF: 0.524

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.4
DANN	Benign	0.63
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	9.6e-7	T
MetaSVM	Benign	-0.93	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.023
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.10
ClinPred		0.0022	T
GERP RS		0.19
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1051130; hg19: chr6-41903782; COSMIC: COSV57827647; COSMIC: COSV57827647;