rs3217901

Variant names:

• chr12-4296223-A-G
• rs3217901
• NM_001759.4:c.721-3637A>G

Variant summary

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

The NM_001759.4(CCND2):​c.721-3637A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.359 in 152,186 control chromosomes in the GnomAD database, including 11,309 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 0.36 (11309 hom., cov: 33)
• Consequence: CCND2 NM_001759.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.197
• Publications: 41 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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.514 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCND2	NM_001759.4	c.721-3637A>G		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.721-3637A>G		intron_variant	Intron 4 of 4	1	NM_001759.4	ENSP00000261254.3
ENSG00000285901	ENST00000674624.1	n.720+7233A>G		intron_variant	Intron 4 of 9			ENSP00000501898.1

Frequencies

GnomAD3 genomes AF: 0.359 AC: 54655 AN: 152068 Hom.: 11313 Cov.: 33

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.510

Gnomad AMR AF: 0.480

Gnomad ASJ AF: 0.394

Gnomad EAS AF: 0.531

Gnomad SAS AF: 0.476

Gnomad FIN AF: 0.461

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.420

Gnomad OTH AF: 0.382

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

GnomAD4 genome AF: 0.359 AC: 54669 AN: 152186 Hom.: 11309 Cov.: 33 AF XY: 0.364 AC XY: 27085 AN XY: 74406

African (AFR) AF: 0.147 AC: 6116 AN: 41530

American (AMR) AF: 0.480 AC: 7345 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.394 AC: 1368 AN: 3468

East Asian (EAS) AF: 0.531 AC: 2749 AN: 5180

South Asian (SAS) AF: 0.476 AC: 2300 AN: 4832

European-Finnish (FIN) AF: 0.461 AC: 4880 AN: 10580

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.420 AC: 28554 AN: 67990

Other (OTH) AF: 0.381 AC: 804 AN: 2112

Alfa AF: 0.397 Hom.: 42277

Bravo AF: 0.354

Asia WGS AF: 0.455 AC: 1585 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.9
DANN	Benign	0.40
PhyloP100		0.20
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: rs3217901; hg19: chr12-4405389;