chr12-4275998-A-C

Variant names:

• chr12-4275998-A-C
• rs1283790151
• NM_001759.4:c.196-7A>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001759.4(CCND2):​c.196-7A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.010 (0 hom., cov: 19)
  • Exomes 𝑓: 0.00094 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CCND2 NM_001759.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001247
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.08
• Publications: 0 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]

ENSG00000285901 (HGNC:):

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

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 12-4275998-A-C is Benign according to our data. Variant chr12-4275998-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 774212.Status of the report is criteria_provided_single_submitter, 1 stars.

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.196-7A>C		splice_region intron	N/A	NP_001750.1	P30279-1
	CCND2-AS1	NR_125790.1		n.126+61T>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCND2	ENST00000261254.8	TSL:1 MANE Select	c.196-7A>C		splice_region intron	N/A	ENSP00000261254.3	P30279-1
	ENSG00000285901	ENST00000674624.1		n.196-7A>C		splice_region intron	N/A	ENSP00000501898.1	A0A6Q8PFP0
	CCND2	ENST00000675880.1		c.196-7A>C		splice_region intron	N/A	ENSP00000502508.1	A0A6Q8PGZ3

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 713 AN: 70460 Hom.: 0 Cov.: 19

Gnomad AFR AF: 0.0122

Gnomad AMI AF: 0.00617

Gnomad AMR AF: 0.0266

Gnomad ASJ AF: 0.00467

Gnomad EAS AF: 0.00628

Gnomad SAS AF: 0.00303

Gnomad FIN AF: 0.0166

Gnomad MID AF: 0.0254

Gnomad NFE AF: 0.00717

Gnomad OTH AF: 0.00996

GnomAD2 exomes AF: 0.000133 AC: 28 AN: 211006 AF XY: 0.000147

Gnomad AFR exome AF: 0.0000758

Gnomad AMR exome AF: 0.000201

Gnomad ASJ exome AF: 0.000249

Gnomad EAS exome AF: 0.0000710

Gnomad FIN exome AF: 0.0000489

Gnomad NFE exome AF: 0.000130

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000941 AC: 1113 AN: 1183276 Hom.: 0 Cov.: 23 AF XY: 0.00110 AC XY: 640 AN XY: 582852

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000372 AC: 10 AN: 26858

American (AMR) AF: 0.00115 AC: 37 AN: 32276

Ashkenazi Jewish (ASJ) AF: 0.00116 AC: 23 AN: 19764

East Asian (EAS) AF: 0.000645 AC: 19 AN: 29446

South Asian (SAS) AF: 0.00405 AC: 232 AN: 57314

European-Finnish (FIN) AF: 0.00177 AC: 72 AN: 40638

Middle Eastern (MID) AF: 0.000208 AC: 1 AN: 4818

European-Non Finnish (NFE) AF: 0.000723 AC: 669 AN: 925050

Other (OTH) AF: 0.00106 AC: 50 AN: 47112

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0101 AC: 715 AN: 70506 Hom.: 0 Cov.: 19 AF XY: 0.0105 AC XY: 346 AN XY: 32964

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0121 AC: 204 AN: 16842

American (AMR) AF: 0.0270 AC: 145 AN: 5374

Ashkenazi Jewish (ASJ) AF: 0.00467 AC: 9 AN: 1926

East Asian (EAS) AF: 0.00630 AC: 19 AN: 3018

South Asian (SAS) AF: 0.00305 AC: 7 AN: 2298

European-Finnish (FIN) AF: 0.0166 AC: 57 AN: 3436

Middle Eastern (MID) AF: 0.0268 AC: 3 AN: 112

European-Non Finnish (NFE) AF: 0.00717 AC: 259 AN: 36100

Other (OTH) AF: 0.00985 AC: 9 AN: 914

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000571 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.55
DANN	Benign	0.59
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000012
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: rs1283790151; hg19: chr12-4385164;