12-4279105-C-T

Variant names:

• chr12-4279105-C-T
• rs3217810
• NM_001759.4:c.571+186C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001759.4(CCND2):​c.571+186C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0866 in 152,184 control chromosomes in the GnomAD database, including 806 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.087 (806 hom., cov: 33)
• Consequence: CCND2 NM_001759.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.339
• Publications: 61 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 12-4279105-C-T is Benign according to our data. Variant chr12-4279105-C-T is described in ClinVar as Benign. ClinVar VariationId is 1220672.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.122 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCND2	NM_001759.4	c.571+186C>T		intron_variant	Intron 3 of 4	ENST00000261254.8	NP_001750.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCND2	ENST00000261254.8	c.571+186C>T		intron_variant	Intron 3 of 4	1	NM_001759.4	ENSP00000261254.3
ENSG00000285901	ENST00000674624.1	n.571+186C>T		intron_variant	Intron 3 of 9			ENSP00000501898.1

Frequencies

GnomAD3 genomes AF: 0.0867 AC: 13179 AN: 152066 Hom.: 807 Cov.: 33

Gnomad AFR AF: 0.0214

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.0779

Gnomad ASJ AF: 0.0740

Gnomad EAS AF: 0.00788

Gnomad SAS AF: 0.0781

Gnomad FIN AF: 0.160

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.124

Gnomad OTH AF: 0.0761

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

GnomAD4 genome AF: 0.0866 AC: 13177 AN: 152184 Hom.: 806 Cov.: 33 AF XY: 0.0866 AC XY: 6441 AN XY: 74368

African (AFR) AF: 0.0214 AC: 887 AN: 41534

American (AMR) AF: 0.0781 AC: 1195 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0740 AC: 257 AN: 3472

East Asian (EAS) AF: 0.00790 AC: 41 AN: 5190

South Asian (SAS) AF: 0.0780 AC: 375 AN: 4808

European-Finnish (FIN) AF: 0.160 AC: 1693 AN: 10562

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.124 AC: 8457 AN: 68006

Other (OTH) AF: 0.0754 AC: 159 AN: 2110

Alfa AF: 0.106 Hom.: 2149

Bravo AF: 0.0766

Asia WGS AF: 0.0280 AC: 100 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 28, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	9.4
DANN	Benign	0.85
PhyloP100		0.34
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: rs3217810; hg19: chr12-4388271;