rs1049612

Variant names:

• chr12-4303596-A-G
• rs1049612
• NM_001759.4:c.*3587A>G

Variant summary

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

The NM_001759.4(CCND2):​c.*3587A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.314 in 233,348 control chromosomes in the GnomAD database, including 13,183 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 0.30 (7839 hom., cov: 31)
  • Exomes 𝑓: 0.34 (5344 hom.)
• Consequence: CCND2 NM_001759.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0250
• Publications: 21 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: Genomics England PanelApp, Ambry Genetics, G2P, ClinGen, 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=-0.8).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.39 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.*3587A>G		3_prime_UTR	Exon 5 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.*3587A>G		3_prime_UTR	Exon 5 of 5	ENSP00000261254.3	P30279-1
	ENSG00000285901	ENST00000674624.1		n.720+14606A>G		intron	N/A	ENSP00000501898.1	A0A6Q8PFP0
	CCND2	ENST00000675880.1		c.*3587A>G		3_prime_UTR	Exon 6 of 6	ENSP00000502508.1	A0A6Q8PGZ3

Frequencies

GnomAD3 genomes AF: 0.299 AC: 45436 AN: 151818 Hom.: 7840 Cov.: 31

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.352

Gnomad AMR AF: 0.286

Gnomad ASJ AF: 0.432

Gnomad EAS AF: 0.0648

Gnomad SAS AF: 0.267

Gnomad FIN AF: 0.326

Gnomad MID AF: 0.529

Gnomad NFE AF: 0.394

Gnomad OTH AF: 0.332

GnomAD4 exome AF: 0.341 AC: 27764 AN: 81412 Hom.: 5344 Cov.: 0 AF XY: 0.347 AC XY: 12991 AN XY: 37476

African (AFR) AF: 0.161 AC: 628 AN: 3898

American (AMR) AF: 0.248 AC: 621 AN: 2502

Ashkenazi Jewish (ASJ) AF: 0.416 AC: 2134 AN: 5126

East Asian (EAS) AF: 0.0926 AC: 1056 AN: 11410

South Asian (SAS) AF: 0.262 AC: 184 AN: 702

European-Finnish (FIN) AF: 0.371 AC: 176 AN: 474

Middle Eastern (MID) AF: 0.476 AC: 234 AN: 492

European-Non Finnish (NFE) AF: 0.406 AC: 20337 AN: 50034

Other (OTH) AF: 0.353 AC: 2394 AN: 6774

GnomAD4 genome AF: 0.299 AC: 45441 AN: 151936 Hom.: 7839 Cov.: 31 AF XY: 0.296 AC XY: 21971 AN XY: 74262

African (AFR) AF: 0.159 AC: 6600 AN: 41410

American (AMR) AF: 0.285 AC: 4355 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.432 AC: 1500 AN: 3472

East Asian (EAS) AF: 0.0651 AC: 337 AN: 5174

South Asian (SAS) AF: 0.268 AC: 1292 AN: 4812

European-Finnish (FIN) AF: 0.326 AC: 3442 AN: 10546

Middle Eastern (MID) AF: 0.524 AC: 153 AN: 292

European-Non Finnish (NFE) AF: 0.394 AC: 26754 AN: 67950

Other (OTH) AF: 0.327 AC: 687 AN: 2100

Alfa AF: 0.381 Hom.: 22595

Bravo AF: 0.292

Asia WGS AF: 0.148 AC: 514 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	12
DANN	Benign	0.63
PhyloP100		-0.025
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1049612;

hg19: chr12-4412762;