12-4275974-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001759.4(CCND2):c.196-31G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.013 (0 hom., cov: 23)
  • Exomes 𝑓: 0.024 (3 hom.)
  • Failed GnomAD Quality Control
• Consequence: CCND2 NM_001759.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.76

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)

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 12-4275974-G-C is Benign according to our data. Variant chr12-4275974-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 1195560.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0601 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCND2	NM_001759.4	c.196-31G>C		intron_variant		ENST00000261254.8
CCND2-AS1	NR_125790.1	n.126+85C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCND2	ENST00000261254.8	c.196-31G>C		intron_variant		1	NM_001759.4	P1
CCND2-AS1	ENST00000663068.1	n.194+85C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1118 AN: 88006 Hom.: 0 Cov.: 23 FAILED QC

Gnomad AFR AF: 0.0160

Gnomad AMI AF: 0.0119

Gnomad AMR AF: 0.0180

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.00701

Gnomad SAS AF: 0.00884

Gnomad FIN AF: 0.0132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0108

Gnomad OTH AF: 0.0161

GnomAD3 exomes AF: 0.00549 AC: 821 AN: 149676 Hom.: 0 AF XY: 0.00490 AC XY: 408 AN XY: 83318

Gnomad AFR exome AF: 0.00913

Gnomad AMR exome AF: 0.0131

Gnomad ASJ exome AF: 0.00604

Gnomad EAS exome AF: 0.00888

Gnomad SAS exome AF: 0.00448

Gnomad FIN exome AF: 0.000733

Gnomad NFE exome AF: 0.00457

Gnomad OTH exome AF: 0.00828

GnomAD4 exome AF: 0.0236 AC: 9927 AN: 420260 Hom.: 3 Cov.: 10 AF XY: 0.0246 AC XY: 5338 AN XY: 216990

Gnomad4 AFR exome AF: 0.0246

Gnomad4 AMR exome AF: 0.0284

Gnomad4 ASJ exome AF: 0.0163

Gnomad4 EAS exome AF: 0.0130

Gnomad4 SAS exome AF: 0.0627

Gnomad4 FIN exome AF: 0.0128

Gnomad4 NFE exome AF: 0.0223

Gnomad4 OTH exome AF: 0.0227

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0127 AC: 1117 AN: 88060 Hom.: 0 Cov.: 23 AF XY: 0.0128 AC XY: 536 AN XY: 41986

Gnomad4 AFR AF: 0.0160

Gnomad4 AMR AF: 0.0180

Gnomad4 ASJ AF: 0.0104

Gnomad4 EAS AF: 0.00703

Gnomad4 SAS AF: 0.00850

Gnomad4 FIN AF: 0.0132

Gnomad4 NFE AF: 0.0108

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.0124 Hom.: 6

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 18, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.68
Dann	Benign	0.41

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: rs770583513; hg19: chr12-4385140;