rs3217795

Variant names:

• chr12-4276898-A-G
• rs3217795
• NM_001759.4:c.411+678A>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.411+678A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0733 in 152,244 control chromosomes in the GnomAD database, including 472 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 0.073 (472 hom., cov: 32)
• Consequence: CCND2 NM_001759.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.52
• 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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0881 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCND2	NM_001759.4	c.411+678A>G		intron_variant	Intron 2 of 4	ENST00000261254.8	NP_001750.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCND2	ENST00000261254.8	c.411+678A>G		intron_variant	Intron 2 of 4	1	NM_001759.4	ENSP00000261254.3
ENSG00000285901	ENST00000674624.1	n.411+678A>G		intron_variant	Intron 2 of 9			ENSP00000501898.1

Frequencies

GnomAD3 genomes AF: 0.0733 AC: 11150 AN: 152126 Hom.: 470 Cov.: 32

Gnomad AFR AF: 0.0480

Gnomad AMI AF: 0.0758

Gnomad AMR AF: 0.0649

Gnomad ASJ AF: 0.0718

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0742

Gnomad FIN AF: 0.105

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.0900

Gnomad OTH AF: 0.0915

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

GnomAD4 genome AF: 0.0733 AC: 11159 AN: 152244 Hom.: 472 Cov.: 32 AF XY: 0.0736 AC XY: 5478 AN XY: 74428

African (AFR) AF: 0.0482 AC: 2002 AN: 41528

American (AMR) AF: 0.0648 AC: 991 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0718 AC: 249 AN: 3468

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5186

South Asian (SAS) AF: 0.0745 AC: 359 AN: 4818

European-Finnish (FIN) AF: 0.105 AC: 1118 AN: 10604

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.0900 AC: 6124 AN: 68028

Other (OTH) AF: 0.0905 AC: 191 AN: 2110

Alfa AF: 0.0809 Hom.: 668

Bravo AF: 0.0698

Asia WGS AF: 0.0300 AC: 105 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.45
DANN	Benign	0.69
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3217795; hg19: chr12-4386064;