12-4274005-G-T

Position:

• chr12-4274005-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001759.4(CCND2):​c.-36G>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 0.000929 in 1,592,612 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (2 hom.)
• Consequence: CCND2 NM_001759.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.929

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 12-4274005-G-T is Benign according to our data. Variant chr12-4274005-G-T is described in ClinVar as [Benign]. Clinvar id is 507367.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00349 (531/152280) while in subpopulation AFR AF= 0.0105 (438/41564). AF 95% confidence interval is 0.00972. There are 0 homozygotes in gnomad4. There are 271 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 531 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCND2	NM_001759.4	c.-36G>T		5_prime_UTR_variant	1/5	ENST00000261254.8
CCND2-AS1	NR_125790.1	n.126+2054C>A		intron_variant, non_coding_transcript_variant
CCND2-AS1	NR_149145.1	n.182+1291C>A		intron_variant, non_coding_transcript_variant
CCND2-AS1	NR_149146.1	n.182+1291C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCND2	ENST00000261254.8	c.-36G>T		5_prime_UTR_variant	1/5	1	NM_001759.4	P1
CCND2-AS1	ENST00000663068.1	n.194+2054C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00348 AC: 529 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.00384

GnomAD3 exomes AF: 0.00114 AC: 257 AN: 225178 Hom.: 0 AF XY: 0.000904 AC XY: 111 AN XY: 122806

Gnomad AFR exome AF: 0.0110

Gnomad AMR exome AF: 0.00112

Gnomad ASJ exome AF: 0.00289

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000690

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000349

Gnomad OTH exome AF: 0.00128

GnomAD4 exome AF: 0.000658 AC: 948 AN: 1440332 Hom.: 2 Cov.: 32 AF XY: 0.000609 AC XY: 435 AN XY: 714868

Gnomad4 AFR exome AF: 0.0110

Gnomad4 AMR exome AF: 0.00132

Gnomad4 ASJ exome AF: 0.00308

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000472

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000323

Gnomad4 OTH exome AF: 0.00140

GnomAD4 genome AF: 0.00349 AC: 531 AN: 152280 Hom.: 0 Cov.: 32 AF XY: 0.00364 AC XY: 271 AN XY: 74458

Gnomad4 AFR AF: 0.0105

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.00380

Alfa AF: 0.00102 Hom.: 0

Bravo AF: 0.00396

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 05, 2017

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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.5
DANN	Benign	0.76
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: rs3217787; hg19: chr12-4383171;