chr12-4274140-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001759.4(CCND2):​c.100G>C​(p.Glu34Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

CCND2
NM_001759.4 missense

Scores

6
8
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.63
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-AS1 (HGNC:49398): (CCND2 antisense RNA 1)

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.963

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CCND2NM_001759.4 linkuse as main transcriptc.100G>C p.Glu34Gln missense_variant 1/5 ENST00000261254.8
CCND2-AS1NR_125790.1 linkuse as main transcriptn.126+1919C>G intron_variant, non_coding_transcript_variant
CCND2-AS1NR_149145.1 linkuse as main transcriptn.182+1156C>G intron_variant, non_coding_transcript_variant
CCND2-AS1NR_149146.1 linkuse as main transcriptn.182+1156C>G intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CCND2ENST00000261254.8 linkuse as main transcriptc.100G>C p.Glu34Gln missense_variant 1/51 NM_001759.4 P1P30279-1
CCND2-AS1ENST00000663068.1 linkuse as main transcriptn.194+1919C>G intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJun 24, 2022Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.86
BayesDel_addAF
Uncertain
0.030
T
BayesDel_noAF
Benign
-0.20
CADD
Pathogenic
31
DANN
Uncertain
1.0
DEOGEN2
Benign
0.42
T
Eigen
Pathogenic
0.84
Eigen_PC
Pathogenic
0.73
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.96
D
M_CAP
Benign
0.054
D
MetaRNN
Pathogenic
0.96
D
MetaSVM
Benign
-0.37
T
MutationAssessor
Pathogenic
3.3
M
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.69
T
PROVEAN
Uncertain
-2.4
N
REVEL
Uncertain
0.45
Sift
Uncertain
0.0020
D
Sift4G
Uncertain
0.016
D
Polyphen
1.0
D
Vest4
0.80
MutPred
0.88
Gain of helix (P = 0.132);
MVP
0.57
MPC
2.1
ClinPred
0.98
D
GERP RS
4.2
Varity_R
0.66
gMVP
0.98

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-4383306; COSMIC: COSV54226173; COSMIC: COSV54226173; API