NM_001759.4:c.570C>G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001759.4(CCND2):​c.570C>G​(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 0.367 in 1,608,466 control chromosomes in the GnomAD database, including 112,564 homozygotes. 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 Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T190T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.32 (8329 hom., cov: 33)
  • Exomes 𝑓: 0.37 (104235 hom.)
• Consequence: CCND2 NM_001759.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.0001498
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.016).
• BP6: Variant 12-4278918-C-G is Benign according to our data. Variant chr12-4278918-C-G is described in ClinVar as Benign. ClinVar VariationId is 380772.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.104 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.389 is higher than 0.05.

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>G	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>G	p.Thr190Thr	splice_region synonymous	Exon 3 of 5	ENSP00000261254.3	P30279-1
	ENSG00000285901	ENST00000674624.1		n.570C>G		splice_region non_coding_transcript_exon	Exon 3 of 10	ENSP00000501898.1	A0A6Q8PFP0
	CCND2	ENST00000675880.1		c.570C>G	p.Thr190Thr	splice_region synonymous	Exon 3 of 6	ENSP00000502508.1	A0A6Q8PGZ3

Frequencies

GnomAD3 genomes AF: 0.316 AC: 48009 AN: 151992 Hom.: 8334 Cov.: 33

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.429

Gnomad AMR AF: 0.318

Gnomad ASJ AF: 0.425

Gnomad EAS AF: 0.0868

Gnomad SAS AF: 0.254

Gnomad FIN AF: 0.365

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.394

Gnomad OTH AF: 0.334

GnomAD2 exomes AF: 0.323 AC: 79825 AN: 246906 AF XY: 0.328

Gnomad AFR exome AF: 0.187

Gnomad AMR exome AF: 0.299

Gnomad ASJ exome AF: 0.417

Gnomad EAS exome AF: 0.0777

Gnomad FIN exome AF: 0.364

Gnomad NFE exome AF: 0.391

Gnomad OTH exome AF: 0.354

GnomAD4 exome AF: 0.373 AC: 542798 AN: 1456356 Hom.: 104235 Cov.: 35 AF XY: 0.370 AC XY: 267958 AN XY: 723734

African (AFR) AF: 0.192 AC: 6423 AN: 33410

American (AMR) AF: 0.302 AC: 13478 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.422 AC: 10998 AN: 26076

East Asian (EAS) AF: 0.155 AC: 6143 AN: 39558

South Asian (SAS) AF: 0.264 AC: 22764 AN: 86112

European-Finnish (FIN) AF: 0.360 AC: 18846 AN: 52364

Middle Eastern (MID) AF: 0.361 AC: 2078 AN: 5756

European-Non Finnish (NFE) AF: 0.398 AC: 440919 AN: 1108314

Other (OTH) AF: 0.352 AC: 21149 AN: 60164

GnomAD4 genome AF: 0.316 AC: 48009 AN: 152110 Hom.: 8329 Cov.: 33 AF XY: 0.312 AC XY: 23211 AN XY: 74346

African (AFR) AF: 0.198 AC: 8206 AN: 41502

American (AMR) AF: 0.318 AC: 4870 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.425 AC: 1475 AN: 3472

East Asian (EAS) AF: 0.0868 AC: 449 AN: 5174

South Asian (SAS) AF: 0.255 AC: 1226 AN: 4812

European-Finnish (FIN) AF: 0.365 AC: 3851 AN: 10552

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.393 AC: 26748 AN: 67986

Other (OTH) AF: 0.329 AC: 695 AN: 2110

Alfa AF: 0.359 Hom.: 6675

Bravo AF: 0.306

Asia WGS AF: 0.133 AC: 466 AN: 3478

EpiCase AF: 0.403

EpiControl AF: 0.406

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.19
DANN	Benign	0.63
PhyloP100		-0.10
Mutation Taster		=75/25	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
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

Other links and lift over

dbSNP: rs3217805; hg19: chr12-4388084; COSMIC: COSV54221448; COSMIC: COSV54221448;