Genetic Variant CCND2:c.-136G>C (chr12-4273158-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The ENST00000676279.1(CCND2):c.-136G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.304 in 152,094 control chromosomes in the GnomAD database, including 7,259 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.30 ( 7259 hom., cov: 32)

Consequence

CCND2
ENST00000676279.1 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.80

Publications

3 publications found

Variant links:

Genes affected

CCND2 (HGNC:1583): (cyclin D2) 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 CDK4 or CDK6 and functions as a regulatory subunit of the complex, whose activity 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. Knockout studies of the homologous gene in mouse suggest the essential roles of this gene in ovarian granulosa and germ cell proliferation. High level expression of this gene was observed in ovarian and testicular tumors. Mutations in this gene are associated with megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3 (MPPH3). [provided by RefSeq, Sep 2014]

CCND2 links:

CCND2-AS1 (HGNC:49398): (CCND2 antisense RNA 1)

CCND2-AS1 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 (BayesDel_noAF=-0.77).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.499 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank
CCND2-AS1	NR_125790.1 link	n.126+2901C>G	intron_variant	Intron 1 of 1
CCND2-AS1	NR_149145.1 link	n.182+2138C>G	intron_variant	Intron 1 of 3
CCND2-AS1	NR_149146.1 link	n.182+2138C>G	intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein	UniProt
CCND2	ENST00000676279.1 link	c.-136G>C	5_prime_UTR_variant	Exon 1 of 6		ENSP00000502597.1	P30279-1
CCND2	ENST00000676411.1 link	c.-40-843G>C	intron_variant	Intron 1 of 5		ENSP00000502654.1	P30279-1
CCND2-AS1	ENST00000537370.2 link	n.401+1864C>G	intron_variant	Intron 1 of 2	4

Frequencies

GnomAD3 genomes

AF:

0.304

AC:

46214

AN:

151976

Hom.:

7260

Cov.:

show subpopulations

Gnomad AFR

AF:

0.218

Gnomad AMI

AF:

0.405

Gnomad AMR

AF:

0.337

Gnomad ASJ

AF:

0.394

Gnomad EAS

AF:

0.516

Gnomad SAS

AF:

0.337

Gnomad FIN

AF:

0.279

Gnomad MID

AF:

0.376

Gnomad NFE

AF:

0.328

Gnomad OTH

AF:

0.333

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.304

AC:

46222

AN:

152094

Hom.:

7259

Cov.:

AF XY:

0.306

AC XY:

22707

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.217

AC:

9025

AN:

41502

American (AMR)

AF:

0.337

AC:

5150

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.394

AC:

1368

AN:

3468

East Asian (EAS)

AF:

0.515

AC:

2654

AN:

5150

South Asian (SAS)

AF:

0.337

AC:

1623

AN:

4816

European-Finnish (FIN)

AF:

0.279

AC:

2958

AN:

10588

Middle Eastern (MID)

AF:

0.377

AC:

110

AN:

292

European-Non Finnish (NFE)

AF:

0.327

AC:

22251

AN:

67954

Other (OTH)

AF:

0.338

AC:

714

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1676

3352

5027

6703

8379

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

476

952

1428

1904

2380

<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:

0.306

Hom.:

868

Bravo

AF:

0.308

Asia WGS

AF:

0.467

AC:

1621

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

3.2

(source)

DANN

Benign

0.69

PhyloP100

1.8

PromoterAI

-0.029

Neutral

(source)

Splicing

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over