rs3217906

Variant names:

• chr12-4296638-G-A
• rs3217906
• NM_001759.4:c.721-3222G>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.721-3222G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.751 in 151,772 control chromosomes in the GnomAD database, including 42,967 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 0.75 (42967 hom., cov: 30)
• Consequence: CCND2 NM_001759.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.231
• Publications: 15 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.904 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCND2	NM_001759.4	c.721-3222G>A		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.721-3222G>A		intron_variant	Intron 4 of 4	1	NM_001759.4	ENSP00000261254.3
ENSG00000285901	ENST00000674624.1	n.720+7648G>A		intron_variant	Intron 4 of 9			ENSP00000501898.1

Frequencies

GnomAD3 genomes AF: 0.751 AC: 113855 AN: 151654 Hom.: 42927 Cov.: 30

Gnomad AFR AF: 0.716

Gnomad AMI AF: 0.593

Gnomad AMR AF: 0.827

Gnomad ASJ AF: 0.687

Gnomad EAS AF: 0.926

Gnomad SAS AF: 0.784

Gnomad FIN AF: 0.755

Gnomad MID AF: 0.687

Gnomad NFE AF: 0.744

Gnomad OTH AF: 0.758

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

GnomAD4 genome AF: 0.751 AC: 113947 AN: 151772 Hom.: 42967 Cov.: 30 AF XY: 0.755 AC XY: 55956 AN XY: 74120

African (AFR) AF: 0.716 AC: 29578 AN: 41326

American (AMR) AF: 0.828 AC: 12636 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.687 AC: 2381 AN: 3468

East Asian (EAS) AF: 0.926 AC: 4768 AN: 5150

South Asian (SAS) AF: 0.785 AC: 3774 AN: 4810

European-Finnish (FIN) AF: 0.755 AC: 7912 AN: 10478

Middle Eastern (MID) AF: 0.690 AC: 203 AN: 294

European-Non Finnish (NFE) AF: 0.744 AC: 50554 AN: 67962

Other (OTH) AF: 0.761 AC: 1601 AN: 2104

Alfa AF: 0.750 Hom.: 54049

Bravo AF: 0.755

Asia WGS AF: 0.884 AC: 3073 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.4
DANN	Benign	0.46
PhyloP100		0.23
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: rs3217906; hg19: chr12-4405804;