12-4288600-G-C

Variant names:

• chr12-4288600-G-C
• rs3217852
• NM_001759.4:c.572-242G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001759.4(CCND2):​c.572-242G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.182 in 152,106 control chromosomes in the GnomAD database, including 2,872 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.18 (2872 hom., cov: 30)
• Consequence: CCND2 NM_001759.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.279
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000285901 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 12-4288600-G-C is Benign according to our data. Variant chr12-4288600-G-C is described in ClinVar as Benign. ClinVar VariationId is 1225707.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.233 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCND2	NM_001759.4	c.572-242G>C		intron_variant	Intron 3 of 4	ENST00000261254.8	NP_001750.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCND2	ENST00000261254.8	c.572-242G>C		intron_variant	Intron 3 of 4	1	NM_001759.4	ENSP00000261254.3
ENSG00000285901	ENST00000674624.1	n.572-242G>C		intron_variant	Intron 3 of 9			ENSP00000501898.1

Frequencies

GnomAD3 genomes AF: 0.183 AC: 27750 AN: 151988 Hom.: 2876 Cov.: 30

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.340

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.230

Gnomad EAS AF: 0.0651

Gnomad SAS AF: 0.176

Gnomad FIN AF: 0.232

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.236

Gnomad OTH AF: 0.196

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

GnomAD4 genome AF: 0.182 AC: 27742 AN: 152106 Hom.: 2872 Cov.: 30 AF XY: 0.180 AC XY: 13374 AN XY: 74348

African (AFR) AF: 0.104 AC: 4318 AN: 41506

American (AMR) AF: 0.143 AC: 2192 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.230 AC: 798 AN: 3472

East Asian (EAS) AF: 0.0653 AC: 338 AN: 5180

South Asian (SAS) AF: 0.175 AC: 845 AN: 4818

European-Finnish (FIN) AF: 0.232 AC: 2451 AN: 10554

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.236 AC: 16014 AN: 67968

Other (OTH) AF: 0.193 AC: 409 AN: 2114

Alfa AF: 0.101 Hom.: 160

Bravo AF: 0.172

Asia WGS AF: 0.0800 AC: 279 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.72
DANN	Benign	0.71
PhyloP100		-0.28
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3217852; hg19: chr12-4397766;