rs3217916

Variant names:

• chr12-4299507-C-T
• rs3217916
• NM_001759.4:c.721-353C>T

Variant summary

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

The NM_001759.4(CCND2):​c.721-353C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.639 in 151,944 control chromosomes in the GnomAD database, including 32,530 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 0.64 (32530 hom., cov: 31)
• Consequence: CCND2 NM_001759.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.696
• Publications: 14 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.72 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCND2	NM_001759.4	c.721-353C>T		intron_variant	Intron 4 of 4	ENST00000261254.8	NP_001750.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCND2	ENST00000261254.8	c.721-353C>T		intron_variant	Intron 4 of 4	1	NM_001759.4	ENSP00000261254.3
ENSG00000285901	ENST00000674624.1	n.720+10517C>T		intron_variant	Intron 4 of 9			ENSP00000501898.1

Frequencies

GnomAD3 genomes AF: 0.639 AC: 97071 AN: 151826 Hom.: 32516 Cov.: 31

Gnomad AFR AF: 0.424

Gnomad AMI AF: 0.876

Gnomad AMR AF: 0.731

Gnomad ASJ AF: 0.779

Gnomad EAS AF: 0.549

Gnomad SAS AF: 0.717

Gnomad FIN AF: 0.739

Gnomad MID AF: 0.813

Gnomad NFE AF: 0.723

Gnomad OTH AF: 0.674

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

GnomAD4 genome AF: 0.639 AC: 97125 AN: 151944 Hom.: 32530 Cov.: 31 AF XY: 0.644 AC XY: 47806 AN XY: 74244

African (AFR) AF: 0.424 AC: 17548 AN: 41374

American (AMR) AF: 0.731 AC: 11178 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.779 AC: 2703 AN: 3470

East Asian (EAS) AF: 0.550 AC: 2839 AN: 5160

South Asian (SAS) AF: 0.718 AC: 3460 AN: 4820

European-Finnish (FIN) AF: 0.739 AC: 7801 AN: 10560

Middle Eastern (MID) AF: 0.810 AC: 238 AN: 294

European-Non Finnish (NFE) AF: 0.723 AC: 49153 AN: 67964

Other (OTH) AF: 0.667 AC: 1408 AN: 2110

Alfa AF: 0.696 Hom.: 110687

Bravo AF: 0.633

Asia WGS AF: 0.577 AC: 2008 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.13
DANN	Benign	0.36
PhyloP100		-0.70
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: rs3217916; hg19: chr12-4408673;