chr12-4275986-T-C

Position:

• chr12-4275986-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001759.4(CCND2):​c.196-19T>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 0.0020 (0 hom., cov: 27)
  • Exomes 𝑓: 0.0022 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CCND2 NM_001759.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.428

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=-0.79).
• BP6: Variant 12-4275986-T-C is Benign according to our data. Variant chr12-4275986-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 2990288.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00219 (1177/537860) while in subpopulation SAS AF= 0.00589 (265/44962). AF 95% confidence interval is 0.00531. There are 0 homozygotes in gnomad4_exome. There are 658 alleles in male gnomad4_exome subpopulation. Median coverage is 14. This position pass quality control queck.
• BS2: High AC in GnomAdExome4 at 1177 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCND2	NM_001759.4	c.196-19T>C		intron_variant		ENST00000261254.8
CCND2-AS1	NR_125790.1	n.126+73A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCND2	ENST00000261254.8	c.196-19T>C		intron_variant		1	NM_001759.4	P1
CCND2-AS1	ENST00000663068.1	n.194+73A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00 AC: 222 AN: 109746 Hom.: 0 Cov.: 27 FAILED QC

Gnomad AFR AF: 0.00300

Gnomad AMI AF: 0.00147

Gnomad AMR AF: 0.00302

Gnomad ASJ AF: 0.000345

Gnomad EAS AF: 0.00329

Gnomad SAS AF: 0.000648

Gnomad FIN AF: 0.00437

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00120

Gnomad OTH AF: 0.00202

GnomAD4 exome AF: 0.00219 AC: 1177 AN: 537860 Hom.: 0 Cov.: 14 AF XY: 0.00239 AC XY: 658 AN XY: 275440

Gnomad4 AFR exome AF: 0.00218

Gnomad4 AMR exome AF: 0.00220

Gnomad4 ASJ exome AF: 0.00167

Gnomad4 EAS exome AF: 0.00164

Gnomad4 SAS exome AF: 0.00589

Gnomad4 FIN exome AF: 0.00191

Gnomad4 NFE exome AF: 0.00176

Gnomad4 OTH exome AF: 0.00302

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00202 AC: 222 AN: 109786 Hom.: 0 Cov.: 27 AF XY: 0.00239 AC XY: 124 AN XY: 51894

Gnomad4 AFR AF: 0.00300

Gnomad4 AMR AF: 0.00301

Gnomad4 ASJ AF: 0.000345

Gnomad4 EAS AF: 0.00330

Gnomad4 SAS AF: 0.000648

Gnomad4 FIN AF: 0.00437

Gnomad4 NFE AF: 0.00120

Gnomad4 OTH AF: 0.00201

Alfa AF: 0.00560 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

Sep 19, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.2
DANN	Benign	0.70
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: rs765683372; hg19: chr12-4385152;