12-4278918-C-G

Position:

• chr12-4278918-C-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001759.4(CCND2):​c.570C>G​(p.Thr190=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.367 in 1,608,466 control chromosomes in the GnomAD database, including 112,564 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (8329 hom., cov: 33)
  • Exomes 𝑓: 0.37 (104235 hom.)
• Consequence: CCND2 NM_001759.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.0001498
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.104

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 12-4278918-C-G is Benign according to our data. Variant chr12-4278918-C-G is described in ClinVar as [Benign]. Clinvar id is 380772.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.104 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.389 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCND2	NM_001759.4	c.570C>G	p.Thr190=	splice_region_variant, synonymous_variant	3/5	ENST00000261254.8	NP_001750.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCND2	ENST00000261254.8	c.570C>G	p.Thr190=	splice_region_variant, synonymous_variant	3/5	1	NM_001759.4	ENSP00000261254	P1

Frequencies

GnomAD3 genomes AF: 0.316 AC: 48009 AN: 151992 Hom.: 8334 Cov.: 33

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.429

Gnomad AMR AF: 0.318

Gnomad ASJ AF: 0.425

Gnomad EAS AF: 0.0868

Gnomad SAS AF: 0.254

Gnomad FIN AF: 0.365

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.394

Gnomad OTH AF: 0.334

GnomAD3 exomes AF: 0.323 AC: 79825 AN: 246906 Hom.: 14077 AF XY: 0.328 AC XY: 43809 AN XY: 133688

Gnomad AFR exome AF: 0.187

Gnomad AMR exome AF: 0.299

Gnomad ASJ exome AF: 0.417

Gnomad EAS exome AF: 0.0777

Gnomad SAS exome AF: 0.259

Gnomad FIN exome AF: 0.364

Gnomad NFE exome AF: 0.391

Gnomad OTH exome AF: 0.354

GnomAD4 exome AF: 0.373 AC: 542798 AN: 1456356 Hom.: 104235 Cov.: 35 AF XY: 0.370 AC XY: 267958 AN XY: 723734

Gnomad4 AFR exome AF: 0.192

Gnomad4 AMR exome AF: 0.302

Gnomad4 ASJ exome AF: 0.422

Gnomad4 EAS exome AF: 0.155

Gnomad4 SAS exome AF: 0.264

Gnomad4 FIN exome AF: 0.360

Gnomad4 NFE exome AF: 0.398

Gnomad4 OTH exome AF: 0.352

GnomAD4 genome AF: 0.316 AC: 48009 AN: 152110 Hom.: 8329 Cov.: 33 AF XY: 0.312 AC XY: 23211 AN XY: 74346

Gnomad4 AFR AF: 0.198

Gnomad4 AMR AF: 0.318

Gnomad4 ASJ AF: 0.425

Gnomad4 EAS AF: 0.0868

Gnomad4 SAS AF: 0.255

Gnomad4 FIN AF: 0.365

Gnomad4 NFE AF: 0.393

Gnomad4 OTH AF: 0.329

Alfa AF: 0.359 Hom.: 6675

Bravo AF: 0.306

Asia WGS AF: 0.133 AC: 466 AN: 3478

EpiCase AF: 0.403

EpiControl AF: 0.406

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 19, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.19
DANN	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
dbscSNV1_RF	Benign	0.0
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: rs3217805; hg19: chr12-4388084; COSMIC: COSV54221448; COSMIC: COSV54221448;