12-4290330-C-T

Variant names:

• chr12-4290330-C-T
• rs3217863
• NM_001759.4:c.720+1340C>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.720+1340C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.098 in 152,182 control chromosomes in the GnomAD database, including 1,444 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 0.098 (1444 hom., cov: 33)
• Consequence: CCND2 NM_001759.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.22
• 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 = 0.297 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCND2	NM_001759.4	c.720+1340C>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.720+1340C>T		intron_variant	Intron 4 of 4	1	NM_001759.4	ENSP00000261254.3
ENSG00000285901	ENST00000674624.1	n.720+1340C>T		intron_variant	Intron 4 of 9			ENSP00000501898.1

Frequencies

GnomAD3 genomes AF: 0.0979 AC: 14893 AN: 152064 Hom.: 1434 Cov.: 33

Gnomad AFR AF: 0.0198

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.283

Gnomad ASJ AF: 0.0664

Gnomad EAS AF: 0.310

Gnomad SAS AF: 0.0839

Gnomad FIN AF: 0.187

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0779

Gnomad OTH AF: 0.0957

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

GnomAD4 genome AF: 0.0980 AC: 14909 AN: 152182 Hom.: 1444 Cov.: 33 AF XY: 0.108 AC XY: 8028 AN XY: 74394

African (AFR) AF: 0.0197 AC: 819 AN: 41532

American (AMR) AF: 0.284 AC: 4342 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0664 AC: 230 AN: 3462

East Asian (EAS) AF: 0.310 AC: 1599 AN: 5164

South Asian (SAS) AF: 0.0827 AC: 399 AN: 4822

European-Finnish (FIN) AF: 0.187 AC: 1974 AN: 10576

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0779 AC: 5300 AN: 68018

Other (OTH) AF: 0.0971 AC: 205 AN: 2112

Alfa AF: 0.0893 Hom.: 2171

Bravo AF: 0.108

Asia WGS AF: 0.166 AC: 576 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	0.35
DANN	Benign	0.90
PhyloP100		-1.2
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: rs3217863; hg19: chr12-4399496;