chr12-4307138-A-G

Variant names:

• chr12-4307138-A-G
• rs4625554
• ENST00000674624.1:n.720+18148A>G

Variant summary

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

The ENST00000674624.1(ENSG00000285901):​n.720+18148A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.307 in 152,148 control chromosomes in the GnomAD database, including 7,669 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 0.31 (7669 hom., cov: 32)
• Consequence: ENSG00000285901 ENST00000674624.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.14
• Publications: 13 publications found

Genes affected

ENSG00000285901 (HGNC:):

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.438 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000674624.1. 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000285901	ENST00000674624.1		n.720+18148A>G		intron	N/A	ENSP00000501898.1	A0A6Q8PFP0
	ENSG00000285901	ENST00000648100.1		n.720+18148A>G		intron	N/A	ENSP00000497536.1	A0A3B3IT44
	CCND2	ENST00000929292.1		c.*336A>G		downstream_gene	N/A	ENSP00000599351.1

Frequencies

GnomAD3 genomes AF: 0.307 AC: 46688 AN: 152028 Hom.: 7652 Cov.: 32

Gnomad AFR AF: 0.239

Gnomad AMI AF: 0.475

Gnomad AMR AF: 0.446

Gnomad ASJ AF: 0.294

Gnomad EAS AF: 0.316

Gnomad SAS AF: 0.361

Gnomad FIN AF: 0.371

Gnomad MID AF: 0.283

Gnomad NFE AF: 0.301

Gnomad OTH AF: 0.313

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.307 AC: 46758 AN: 152148 Hom.: 7669 Cov.: 32 AF XY: 0.313 AC XY: 23279 AN XY: 74366

African (AFR) AF: 0.240 AC: 9956 AN: 41494

American (AMR) AF: 0.447 AC: 6841 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.294 AC: 1019 AN: 3470

East Asian (EAS) AF: 0.316 AC: 1641 AN: 5186

South Asian (SAS) AF: 0.361 AC: 1741 AN: 4822

European-Finnish (FIN) AF: 0.371 AC: 3916 AN: 10556

Middle Eastern (MID) AF: 0.284 AC: 83 AN: 292

European-Non Finnish (NFE) AF: 0.301 AC: 20469 AN: 68004

Other (OTH) AF: 0.311 AC: 659 AN: 2116

Alfa AF: 0.303 Hom.: 24172

Bravo AF: 0.313

Asia WGS AF: 0.337 AC: 1173 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.029
DANN	Benign	0.41
PhyloP100		-1.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4625554; hg19: chr12-4416304;