12-4275678-T-G

Position:

• chr12-4275678-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001759.4(CCND2):​c.196-327T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0143 in 151,400 control chromosomes in the GnomAD database, including 22 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 0.014 (22 hom., cov: 29)
• Consequence: CCND2 NM_001759.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.509

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]

(HGNC:):

CCND2-AS1 (HGNC:49398): (CCND2 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0143 (2172/151400) while in subpopulation NFE AF= 0.0222 (1503/67790). AF 95% confidence interval is 0.0212. There are 22 homozygotes in gnomad4. There are 1037 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2172 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCND2	NM_001759.4	c.196-327T>G		intron_variant		ENST00000261254.8	NP_001750.1
CCND2-AS1	NR_125790.1	n.126+381A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCND2	ENST00000261254.8	c.196-327T>G		intron_variant		1	NM_001759.4	ENSP00000261254	P1
	ENST00000702726.1	n.78A>C		non_coding_transcript_exon_variant	1/1
CCND2-AS1	ENST00000663068.1	n.194+381A>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0144 AC: 2171 AN: 151276 Hom.: 22 Cov.: 29

Gnomad AFR AF: 0.00336

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0106

Gnomad ASJ AF: 0.00894

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00315

Gnomad FIN AF: 0.0272

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0222

Gnomad OTH AF: 0.0111

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

GnomAD4 genome AF: 0.0143 AC: 2172 AN: 151400 Hom.: 22 Cov.: 29 AF XY: 0.0140 AC XY: 1037 AN XY: 73998

Gnomad4 AFR AF: 0.00335

Gnomad4 AMR AF: 0.0106

Gnomad4 ASJ AF: 0.00894

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00315

Gnomad4 FIN AF: 0.0272

Gnomad4 NFE AF: 0.0222

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.0177 Hom.: 6

Bravo AF: 0.0119

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	11
DANN	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs76895963; hg19: chr12-4384844;