chr12-4281206-T-A

Variant names:

• chr12-4281206-T-A
• rs3217820
• NM_001759.4:c.571+2287T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001759.4(CCND2):​c.571+2287T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.282 in 152,184 control chromosomes in the GnomAD database, including 6,812 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 0.28 (6812 hom., cov: 32)
• Consequence: CCND2 NM_001759.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0930
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.359 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCND2	NM_001759.4	c.571+2287T>A		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.571+2287T>A		intron_variant	Intron 3 of 4	1	NM_001759.4	ENSP00000261254.3
ENSG00000285901	ENST00000674624.1	n.571+2287T>A		intron_variant	Intron 3 of 9			ENSP00000501898.1

Frequencies

GnomAD3 genomes AF: 0.282 AC: 42867 AN: 152066 Hom.: 6817 Cov.: 32

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.306

Gnomad AMR AF: 0.257

Gnomad ASJ AF: 0.431

Gnomad EAS AF: 0.0448

Gnomad SAS AF: 0.243

Gnomad FIN AF: 0.317

Gnomad MID AF: 0.491

Gnomad NFE AF: 0.363

Gnomad OTH AF: 0.302

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

GnomAD4 genome AF: 0.282 AC: 42865 AN: 152184 Hom.: 6812 Cov.: 32 AF XY: 0.280 AC XY: 20796 AN XY: 74400

African (AFR) AF: 0.168 AC: 6957 AN: 41504

American (AMR) AF: 0.256 AC: 3916 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.431 AC: 1494 AN: 3468

East Asian (EAS) AF: 0.0449 AC: 233 AN: 5188

South Asian (SAS) AF: 0.244 AC: 1178 AN: 4830

European-Finnish (FIN) AF: 0.317 AC: 3359 AN: 10592

Middle Eastern (MID) AF: 0.486 AC: 143 AN: 294

European-Non Finnish (NFE) AF: 0.363 AC: 24678 AN: 67986

Other (OTH) AF: 0.297 AC: 628 AN: 2114

Alfa AF: 0.165 Hom.: 326

Bravo AF: 0.272

Asia WGS AF: 0.129 AC: 451 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.3
DANN	Benign	0.75
PhyloP100		-0.093
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: rs3217820; hg19: chr12-4390372;