12-4290804-G-A

Variant names:

• chr12-4290804-G-A
• rs3217869
• NM_001759.4:c.720+1814G>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.720+1814G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.5 in 152,002 control chromosomes in the GnomAD database, including 20,363 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 0.50 (20363 hom., cov: 32)
• Consequence: CCND2 NM_001759.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.181
• Publications: 17 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=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.868 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCND2	NM_001759.4	c.720+1814G>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.720+1814G>A		intron_variant	Intron 4 of 4	1	NM_001759.4	ENSP00000261254.3
ENSG00000285901	ENST00000674624.1	n.720+1814G>A		intron_variant	Intron 4 of 9			ENSP00000501898.1

Frequencies

GnomAD3 genomes AF: 0.500 AC: 75928 AN: 151884 Hom.: 20301 Cov.: 32

Gnomad AFR AF: 0.612

Gnomad AMI AF: 0.294

Gnomad AMR AF: 0.605

Gnomad ASJ AF: 0.295

Gnomad EAS AF: 0.890

Gnomad SAS AF: 0.558

Gnomad FIN AF: 0.444

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.398

Gnomad OTH AF: 0.470

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

GnomAD4 genome AF: 0.500 AC: 76055 AN: 152002 Hom.: 20363 Cov.: 32 AF XY: 0.507 AC XY: 37660 AN XY: 74280

African (AFR) AF: 0.612 AC: 25381 AN: 41448

American (AMR) AF: 0.606 AC: 9271 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.295 AC: 1022 AN: 3470

East Asian (EAS) AF: 0.890 AC: 4594 AN: 5162

South Asian (SAS) AF: 0.558 AC: 2682 AN: 4810

European-Finnish (FIN) AF: 0.444 AC: 4685 AN: 10554

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.398 AC: 27072 AN: 67964

Other (OTH) AF: 0.477 AC: 1003 AN: 2104

Alfa AF: 0.445 Hom.: 32883

Bravo AF: 0.517

Asia WGS AF: 0.774 AC: 2689 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.5
DANN	Benign	0.74
PhyloP100		-0.18
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: rs3217869; hg19: chr12-4399970;