rs142170178

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001759.4(CCND2):c.785G>A(p.Arg262His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00068 in 1,614,118 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R262C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0011 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00064 ( 5 hom. )

Consequence

CCND2
NM_001759.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.10

Publications

9 publications found

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 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

CCND2 links:

ENSG00000285901 (HGNC:):

ENSG00000285901 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008829623).

BP6

Variant 12-4299924-G-A is Benign according to our data. Variant chr12-4299924-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 376994.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0011 (168/152268) while in subpopulation AMR AF = 0.00124 (19/15296). AF 95% confidence interval is 0.000813. There are 1 homozygotes in GnomAd4. There are 97 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 168 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCND2	NM_001759.4 link	c.785G>A	p.Arg262His	missense_variant	Exon 5 of 5	ENST00000261254.8	NP_001750.1	P30279-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCND2	ENST00000261254.8 link	c.785G>A	p.Arg262His	missense_variant	Exon 5 of 5	1	NM_001759.4	ENSP00000261254.3		P30279-1
ENSG00000285901	ENST00000674624.1 link	n.720+10934G>A		intron_variant	Intron 4 of 9			ENSP00000501898.1		A0A6Q8PFP0

Frequencies

GnomAD3 genomes

AF:

0.00110

AC:

168

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000652

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00764

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000559

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.00112

AC:

282

AN:

251364

AF XY:

0.00108

show subpopulations

Gnomad AFR exome

AF:

0.000861

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00749

Gnomad NFE exome

AF:

0.000774

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.000635

AC:

929

AN:

1461850

Hom.:

Cov.:

AF XY:

0.000593

AC XY:

431

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.000508

AC:

AN:

33476

American (AMR)

AF:

0.000179

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000927

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00693

AC:

370

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000425

AC:

473

AN:

1111984

Other (OTH)

AF:

0.000844

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

102

152

203

254

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00110

AC:

168

AN:

152268

Hom.:

Cov.:

AF XY:

0.00130

AC XY:

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.000650

AC:

AN:

41544

American (AMR)

AF:

0.00124

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00764

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000559

AC:

AN:

68030

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000621

Hom.:

Bravo

AF:

0.000654

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00112

AC:

136

EpiCase

AF:

0.000273

EpiControl

AF:

0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Nov 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CCND2: BP4, BS1, BS2 -

Dec 30, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 23, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 29642553) -

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.33

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.24

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.65

M_CAP

Benign

0.013

MetaRNN

Benign

0.0088

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

PhyloP100

3.1

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.29

REVEL

Benign

0.063

Sift

Benign

0.14

Sift4G

Benign

0.17

Polyphen

0.014

Vest4

0.16

MVP

0.36

MPC

1.2

ClinPred

0.013

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.041

gMVP

0.27

Mutation Taster

=95/5

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over