Genetic Variant CCND2:p.Leu38Arg (chr12-4274153-T-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001759.4(CCND2):c.113T>G(p.Leu38Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L38L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

CCND2
NM_001759.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.12

Publications

0 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 links:

ENSG00000285901 (HGNC:):

ENSG00000285901 links:

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

CCND2-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.36180246).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001759.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CCND2	NM_001759.4	MANE Select	c.113T>G	p.Leu38Arg	missense	Exon 1 of 5	NP_001750.1	P30279-1
CCND2-AS1	NR_125790.1		n.126+1906A>C		intron	N/A
CCND2-AS1	NR_149145.1		n.182+1143A>C		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CCND2	ENST00000261254.8	TSL:1 MANE Select	c.113T>G	p.Leu38Arg	missense	Exon 1 of 5	ENSP00000261254.3	P30279-1
ENSG00000285901	ENST00000674624.1		n.113T>G		non_coding_transcript_exon	Exon 1 of 10	ENSP00000501898.1	A0A6Q8PFP0
CCND2	ENST00000675880.1		c.113T>G	p.Leu38Arg	missense	Exon 1 of 6	ENSP00000502508.1	A0A6Q8PGZ3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.35

Eigen

Uncertain

0.20

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.040

MetaRNN

Benign

0.36

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.75

PhyloP100

3.1

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.26

Sift

Uncertain

0.025

Sift4G

Uncertain

0.053

Polyphen

0.92

Vest4

0.34

MutPred

0.47

Loss of catalytic residue at L38 (P = 0.0154)

MVP

0.85

MPC

2.4

ClinPred

0.88

GERP RS

3.0

PromoterAI

-0.038

Neutral

(source)

Varity_R

0.40

gMVP

0.93

Mutation Taster

=73/27

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over