12-4278918-C-T

Variant names:

• chr12-4278918-C-T
• rs3217805
• NM_001759.4:c.570C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP7 BS2

The NM_001759.4(CCND2):​c.570C>T​(p.Thr190Thr) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000755 in 1,456,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. T190T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: CCND2 NM_001759.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.0003185
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.104
• Publications: 31 publications found

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 Gene-Disease associations (from GenCC):

• megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000285901 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.147).
• BP7: Synonymous conserved (PhyloP=-0.104 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 11 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001759.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCND2	NM_001759.4	MANE Select	c.570C>T	p.Thr190Thr	splice_region synonymous	Exon 3 of 5	NP_001750.1	P30279-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCND2	ENST00000261254.8	TSL:1 MANE Select	c.570C>T	p.Thr190Thr	splice_region synonymous	Exon 3 of 5	ENSP00000261254.3	P30279-1
	ENSG00000285901	ENST00000674624.1		n.570C>T		splice_region non_coding_transcript_exon	Exon 3 of 10	ENSP00000501898.1	A0A6Q8PFP0
	CCND2	ENST00000675880.1		c.570C>T	p.Thr190Thr	splice_region synonymous	Exon 3 of 6	ENSP00000502508.1	A0A6Q8PGZ3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000810 AC: 2 AN: 246906 AF XY: 0.00000748

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000904

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000755 AC: 11 AN: 1456798 Hom.: 0 Cov.: 35 AF XY: 0.00000967 AC XY: 7 AN XY: 723956

African (AFR) AF: 0.00 AC: 0 AN: 33422

American (AMR) AF: 0.0000224 AC: 1 AN: 44624

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39562

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000631 AC: 7 AN: 1108620

Other (OTH) AF: 0.00 AC: 0 AN: 60186

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 6675

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.38
DANN	Benign	0.79
PhyloP100		-0.10

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00032
dbscSNV1_RF	Benign	0.036
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

Other links and lift over

dbSNP: rs3217805; hg19: chr12-4388084;