12-4275998-A-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001759.4(CCND2):c.196-7A>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.010 (0 hom., cov: 19)
  • Exomes 𝑓: 0.00094 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CCND2 NM_001759.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001247
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.08

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 12-4275998-A-C is Benign according to our data. Variant chr12-4275998-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 774212.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCND2	NM_001759.4	c.196-7A>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000261254.8
CCND2-AS1	NR_125790.1	n.126+61T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCND2	ENST00000261254.8	c.196-7A>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001759.4	P1
CCND2-AS1	ENST00000663068.1	n.194+61T>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00 AC: 713 AN: 70460 Hom.: 0 Cov.: 19 FAILED QC

Gnomad AFR AF: 0.0122

Gnomad AMI AF: 0.00617

Gnomad AMR AF: 0.0266

Gnomad ASJ AF: 0.00467

Gnomad EAS AF: 0.00628

Gnomad SAS AF: 0.00303

Gnomad FIN AF: 0.0166

Gnomad MID AF: 0.0254

Gnomad NFE AF: 0.00717

Gnomad OTH AF: 0.00996

GnomAD3 exomes AF: 0.000133 AC: 28 AN: 211006 Hom.: 0 AF XY: 0.000147 AC XY: 17 AN XY: 115528

Gnomad AFR exome AF: 0.0000758

Gnomad AMR exome AF: 0.000201

Gnomad ASJ exome AF: 0.000249

Gnomad EAS exome AF: 0.0000710

Gnomad SAS exome AF: 0.000194

Gnomad FIN exome AF: 0.0000489

Gnomad NFE exome AF: 0.000130

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000941 AC: 1113 AN: 1183276 Hom.: 0 Cov.: 23 AF XY: 0.00110 AC XY: 640 AN XY: 582852

Gnomad4 AFR exome AF: 0.000372

Gnomad4 AMR exome AF: 0.00115

Gnomad4 ASJ exome AF: 0.00116

Gnomad4 EAS exome AF: 0.000645

Gnomad4 SAS exome AF: 0.00405

Gnomad4 FIN exome AF: 0.00177

Gnomad4 NFE exome AF: 0.000723

Gnomad4 OTH exome AF: 0.00106

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0101 AC: 715 AN: 70506 Hom.: 0 Cov.: 19 AF XY: 0.0105 AC XY: 346 AN XY: 32964

Gnomad4 AFR AF: 0.0121

Gnomad4 AMR AF: 0.0270

Gnomad4 ASJ AF: 0.00467

Gnomad4 EAS AF: 0.00630

Gnomad4 SAS AF: 0.00305

Gnomad4 FIN AF: 0.0166

Gnomad4 NFE AF: 0.00717

Gnomad4 OTH AF: 0.00985

Alfa AF: 0.000571 Hom.: 0

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

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.55
Dann	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000012
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: rs1283790151; hg19: chr12-4385164;