dbSNP rs1051130: CCND3:p.Ser259Ala (chr6-41936044-A-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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. 13/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.62 ( 29837 hom., cov: 32)

Exomes 𝑓: 0.55 ( 223207 hom. )

Consequence

CCND3
NM_001760.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.143

Publications

79 publications found

Variant links:

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 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
CCND3	NM_001760.5 link	c.775T>G	p.Ser259Ala	missense_variant	Exon 5 of 5	ENST00000372991.9	NP_001751.1	P30281-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCND3	ENST00000372991.9 link	c.775T>G	p.Ser259Ala	missense_variant	Exon 5 of 5	1	NM_001760.5	ENSP00000362082.5		P30281-1

Frequencies

GnomAD3 genomes

AF:

0.615

AC:

93438

AN:

151858

Hom.:

29794

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.538

AC:

134150

AN:

249276

AF XY:

0.532

show subpopulations

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 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.:

AF XY:

0.546

AC XY:

396878

AN XY:

726666

show subpopulations

African (AFR)

AF:

0.808

AC:

27059

AN:

33476

American (AMR)

AF:

0.471

AC:

20999

AN:

44574

Ashkenazi Jewish (ASJ)

AF:

0.562

AC:

14637

AN:

26042

East Asian (EAS)

AF:

0.495

AC:

19628

AN:

39680

South Asian (SAS)

AF:

0.450

AC:

38752

AN:

86196

European-Finnish (FIN)

AF:

0.545

AC:

28989

AN:

53202

Middle Eastern (MID)

AF:

0.476

AC:

2730

AN:

5732

European-Non Finnish (NFE)

AF:

0.555

AC:

616442

AN:

1111460

Other (OTH)

AF:

0.561

AC:

33845

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

19293

38586

57878

77171

96464

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17384

34768

52152

69536

86920

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.615

AC:

93523

AN:

151976

Hom.:

29837

Cov.:

AF XY:

0.612

AC XY:

45436

AN XY:

74252

show subpopulations

African (AFR)

AF:

0.805

AC:

33376

AN:

41466

American (AMR)

AF:

0.540

AC:

8246

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.558

AC:

1934

AN:

3464

East Asian (EAS)

AF:

0.523

AC:

2688

AN:

5142

South Asian (SAS)

AF:

0.456

AC:

2198

AN:

4816

European-Finnish (FIN)

AF:

0.546

AC:

5772

AN:

10572

Middle Eastern (MID)

AF:

0.561

AC:

165

AN:

294

European-Non Finnish (NFE)

AF:

0.551

AC:

37415

AN:

67934

Other (OTH)

AF:

0.597

AC:

1258

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1771

3542

5312

7083

8854

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

752

1504

2256

3008

3760

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

BayesDel_noAF

Benign

-0.80

CADD

Benign

3.4

(source)

DANN

Benign

0.63

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.20

MetaRNN

Benign

9.6e-7

MetaSVM

Benign

-0.93

PhyloP100

0.14

PROVEAN

Benign

-1.8

REVEL

Benign

0.023

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Vest4

0.10

ClinPred

0.0022

GERP RS

0.19

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.058

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over