rs587777622

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PM5PP3_ModeratePP5

The NM_001759.4(CCND2):c.842C>G(p.Pro281Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P281A) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CCND2
NM_001759.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1O:1

Conservation

PhyloP100: 7.18

Variant links:

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 links:

ENSG00000285901 (HGNC:):

ENSG00000285901 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-4299980-C-G is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.895

PP5

Variant 12-4299981-C-G is Pathogenic according to our data. Variant chr12-4299981-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 143985.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, not_provided=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCND2	NM_001759.4 linkuse as main transcript	c.842C>G	p.Pro281Arg	missense_variant	5/5	ENST00000261254.8	NP_001750.1	P30279-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCND2	ENST00000261254.8 linkuse as main transcript	c.842C>G	p.Pro281Arg	missense_variant	5/5	1	NM_001759.4	ENSP00000261254.3		P30279-1
ENSG00000285901	ENST00000674624.1 linkuse as main transcript	n.720+10991C>G		intron_variant				ENSP00000501898.1		A0A6Q8PFP0

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152170

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461802

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74340

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3

Pathogenic:1Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2014	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 21, 2020

For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect CCND2 protein function (PMID: 24705253). This variant has been observed in individual(s) with clinical features of megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndrome (PMID: 24705253, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 143985). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with arginine at codon 281 of the CCND2 protein (p.Pro281Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. -

CCND2-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 15, 2023

The CCND2 c.842C>G variant is predicted to result in the amino acid substitution p.Pro281Arg. This variant, as well as additional variants at the same amino acid (p.Pro281Ser, p.Pro281Leu, and p.Pro281Ala) have been been documented in individuals with megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH) (Mirzaa et al. 2014. PubMed ID:24705253; Supplementary Table 3, Patient 21, Helbig et al. 2016. PubMed ID: 26795593; Sameshima et al. 2020. PubMed ID: 31957131). Of note, these variants were documented as de novo in some cases (Mirzaa et al. 2014. PubMed ID:24705253; Supplementary Table 3, Patient 21, Helbig et al. 2016. PubMed ID: 26795593) and in others inheritance was not noted or not determined. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. While this variant may be causative, given the mosaic nature, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.89

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.29

MetaRNN

Pathogenic

0.90

MetaSVM

Benign

-0.34

MutationAssessor

Pathogenic

3.4

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-8.0

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.86

MutPred

0.60

Gain of catalytic residue at P281 (P = 0.0766);

MVP

0.62

MPC

2.2

ClinPred

1.0

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.88

gMVP

0.88

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over