12-4273870-C-T

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.-171C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.58 in 661,906 control chromosomes in the GnomAD database, including 112,200 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.58 (25784 hom., cov: 31)
  • Exomes 𝑓: 0.58 (86416 hom.)
• Consequence: CCND2 NM_001759.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.88

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=-0.81).
• BP6: Variant 12-4273870-C-T is Benign according to our data. Variant chr12-4273870-C-T is described in ClinVar as [Benign]. Clinvar id is 678294.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.688 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCND2	NM_001759.4	c.-171C>T		5_prime_UTR_variant	1/5	ENST00000261254.8
CCND2-AS1	NR_125790.1	n.126+2189G>A		intron_variant, non_coding_transcript_variant
CCND2-AS1	NR_149145.1	n.182+1426G>A		intron_variant, non_coding_transcript_variant
CCND2-AS1	NR_149146.1	n.182+1426G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCND2	ENST00000261254.8	c.-171C>T		5_prime_UTR_variant	1/5	1	NM_001759.4	P1
CCND2-AS1	ENST00000663068.1	n.194+2189G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.580 AC: 88116 AN: 151860 Hom.: 25742 Cov.: 31

Gnomad AFR AF: 0.557

Gnomad AMI AF: 0.698

Gnomad AMR AF: 0.667

Gnomad ASJ AF: 0.624

Gnomad EAS AF: 0.708

Gnomad SAS AF: 0.461

Gnomad FIN AF: 0.544

Gnomad MID AF: 0.639

Gnomad NFE AF: 0.575

Gnomad OTH AF: 0.600

GnomAD4 exome AF: 0.579 AC: 295474 AN: 509928 Hom.: 86416 Cov.: 6 AF XY: 0.575 AC XY: 153040 AN XY: 266150

Gnomad4 AFR exome AF: 0.555

Gnomad4 AMR exome AF: 0.686

Gnomad4 ASJ exome AF: 0.631

Gnomad4 EAS exome AF: 0.633

Gnomad4 SAS exome AF: 0.481

Gnomad4 FIN exome AF: 0.541

Gnomad4 NFE exome AF: 0.583

Gnomad4 OTH exome AF: 0.597

GnomAD4 genome AF: 0.580 AC: 88219 AN: 151978 Hom.: 25784 Cov.: 31 AF XY: 0.581 AC XY: 43193 AN XY: 74324

Gnomad4 AFR AF: 0.557

Gnomad4 AMR AF: 0.667

Gnomad4 ASJ AF: 0.624

Gnomad4 EAS AF: 0.707

Gnomad4 SAS AF: 0.461

Gnomad4 FIN AF: 0.544

Gnomad4 NFE AF: 0.575

Gnomad4 OTH AF: 0.603

Alfa AF: 0.593 Hom.: 22582

Bravo AF: 0.599

Asia WGS AF: 0.617 AC: 2147 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	7.4
Dann	Benign	0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs1049606; hg19: chr12-4383036; COSMIC: COSV54222306; COSMIC: COSV54222306;