12-4294992-G-A

Position:

• chr12-4294992-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001759.4(CCND2):​c.721-4868G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.291 in 152,112 control chromosomes in the GnomAD database, including 7,150 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.29 (7150 hom., cov: 32)
• Consequence: CCND2 NM_001759.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.192

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.366 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCND2	NM_001759.4	c.721-4868G>A		intron_variant		ENST00000261254.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCND2	ENST00000261254.8	c.721-4868G>A		intron_variant		1	NM_001759.4	P1

Frequencies

GnomAD3 genomes AF: 0.291 AC: 44188 AN: 151994 Hom.: 7151 Cov.: 32

Gnomad AFR AF: 0.183

Gnomad AMI AF: 0.289

Gnomad AMR AF: 0.259

Gnomad ASJ AF: 0.454

Gnomad EAS AF: 0.0536

Gnomad SAS AF: 0.250

Gnomad FIN AF: 0.323

Gnomad MID AF: 0.494

Gnomad NFE AF: 0.370

Gnomad OTH AF: 0.316

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

GnomAD4 genome AF: 0.291 AC: 44192 AN: 152112 Hom.: 7150 Cov.: 32 AF XY: 0.288 AC XY: 21412 AN XY: 74352

Gnomad4 AFR AF: 0.183

Gnomad4 AMR AF: 0.258

Gnomad4 ASJ AF: 0.454

Gnomad4 EAS AF: 0.0537

Gnomad4 SAS AF: 0.251

Gnomad4 FIN AF: 0.323

Gnomad4 NFE AF: 0.370

Gnomad4 OTH AF: 0.312

Alfa AF: 0.366 Hom.: 11389

Bravo AF: 0.282

Asia WGS AF: 0.137 AC: 480 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.1
DANN	Benign	0.48

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

Other links and lift over

dbSNP: rs3217896; hg19: chr12-4404158;