12-4302473-C-T

Variant names:

• chr12-4302473-C-T
• rs3217925
• NM_001759.4:c.*2464C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001759.4(CCND2):​c.*2464C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 232,680 control chromosomes in the GnomAD database, including 7,941 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.26 (5194 hom., cov: 30)
  • Exomes 𝑓: 0.26 (2747 hom.)
• Consequence: CCND2 NM_001759.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.178
• Publications: 16 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: Ambry Genetics, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000285901 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.333 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCND2	NM_001759.4	MANE Select	c.*2464C>T		3_prime_UTR	Exon 5 of 5	NP_001750.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCND2	ENST00000261254.8	TSL:1 MANE Select	c.*2464C>T		3_prime_UTR	Exon 5 of 5	ENSP00000261254.3
	ENSG00000285901	ENST00000674624.1		n.720+13483C>T		intron	N/A	ENSP00000501898.1
	CCND2	ENST00000675468.1		n.3258C>T		non_coding_transcript_exon	Exon 5 of 5

Frequencies

GnomAD3 genomes AF: 0.258 AC: 39167 AN: 151828 Hom.: 5187 Cov.: 30

Gnomad AFR AF: 0.294

Gnomad AMI AF: 0.115

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.193

Gnomad EAS AF: 0.347

Gnomad SAS AF: 0.257

Gnomad FIN AF: 0.245

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.252

Gnomad OTH AF: 0.244

GnomAD4 exome AF: 0.257 AC: 20718 AN: 80734 Hom.: 2747 Cov.: 0 AF XY: 0.255 AC XY: 9451 AN XY: 37104

African (AFR) AF: 0.299 AC: 1162 AN: 3892

American (AMR) AF: 0.193 AC: 480 AN: 2488

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 997 AN: 5112

East Asian (EAS) AF: 0.341 AC: 3878 AN: 11368

South Asian (SAS) AF: 0.284 AC: 199 AN: 700

European-Finnish (FIN) AF: 0.258 AC: 16 AN: 62

Middle Eastern (MID) AF: 0.132 AC: 65 AN: 492

European-Non Finnish (NFE) AF: 0.247 AC: 12296 AN: 49870

Other (OTH) AF: 0.241 AC: 1625 AN: 6750

GnomAD4 genome AF: 0.258 AC: 39193 AN: 151946 Hom.: 5194 Cov.: 30 AF XY: 0.256 AC XY: 18985 AN XY: 74244

African (AFR) AF: 0.294 AC: 12192 AN: 41440

American (AMR) AF: 0.193 AC: 2946 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.193 AC: 669 AN: 3468

East Asian (EAS) AF: 0.347 AC: 1780 AN: 5132

South Asian (SAS) AF: 0.256 AC: 1231 AN: 4814

European-Finnish (FIN) AF: 0.245 AC: 2583 AN: 10550

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.252 AC: 17114 AN: 67958

Other (OTH) AF: 0.252 AC: 531 AN: 2108

Alfa AF: 0.246 Hom.: 10240

Bravo AF: 0.251

Asia WGS AF: 0.327 AC: 1137 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.4
DANN	Benign	0.72
PhyloP100		-0.18
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3217925; hg19: chr12-4411639;