13-36437880-C-A

Position:

• chr13-36437880-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000255465.8(CCNA1):​c.412+5C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0025 in 1,612,080 control chromosomes in the GnomAD database, including 67 homozygotes. 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (29 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (38 hom.)
• Consequence: CCNA1 ENST00000255465.8 splice_region, intron
• Scores: Splicing: ADA: 0.0001210
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.170

Genes affected

CCNA1 (HGNC:1577): (cyclin A1) 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. The cyclin encoded by this gene was shown to be expressed in testis and brain, as well as in several leukemic cell lines, and is thought to primarily function in the control of the germline meiotic cell cycle. This cyclin binds both CDK2 and CDC2 kinases, which give two distinct kinase activities, one appearing in S phase, the other in G2, and thus regulate separate functions in cell cycle. This cyclin was found to bind to important cell cycle regulators, such as Rb family proteins, transcription factor E2F-1, and the p21 family proteins. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 13-36437880-C-A is Benign according to our data. Variant chr13-36437880-C-A is described in ClinVar as [Benign]. Clinvar id is 781985.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0104 (1585/152328) while in subpopulation AFR AF= 0.034 (1413/41578). AF 95% confidence interval is 0.0325. There are 29 homozygotes in gnomad4. There are 762 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 29 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCNA1	NM_001111045.4	c.412+5C>A		splice_region_variant, intron_variant			NP_001104515.2
CCNA1	NM_001111046.2	c.412+5C>A		splice_region_variant, intron_variant			NP_001104516.1
CCNA1	NM_001111047.2	c.412+5C>A		splice_region_variant, intron_variant			NP_001104517.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCNA1	ENST00000255465.8	c.412+5C>A		splice_region_variant, intron_variant		1		ENSP00000255465.5
CCNA1	ENST00000625767.2	c.412+5C>A		splice_region_variant, intron_variant		1		ENSP00000486017.2
CCNA1	ENST00000440264.5	c.412+5C>A		splice_region_variant, intron_variant		2		ENSP00000400666.1
CCNA1	ENST00000630422.2	c.412+5C>A		splice_region_variant, intron_variant		2		ENSP00000486482.1

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1567 AN: 152210 Hom.: 29 Cov.: 33

Gnomad AFR AF: 0.0337

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00517

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.00861

GnomAD3 exomes AF: 0.00333 AC: 833 AN: 249864 Hom.: 14 AF XY: 0.00270 AC XY: 364 AN XY: 135016

Gnomad AFR exome AF: 0.0351

Gnomad AMR exome AF: 0.00337

Gnomad ASJ exome AF: 0.00405

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000132

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000734

Gnomad OTH exome AF: 0.00312

GnomAD4 exome AF: 0.00168 AC: 2453 AN: 1459752 Hom.: 38 Cov.: 32 AF XY: 0.00155 AC XY: 1123 AN XY: 725840

Gnomad4 AFR exome AF: 0.0386

Gnomad4 AMR exome AF: 0.00363

Gnomad4 ASJ exome AF: 0.00528

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000163

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000500

Gnomad4 OTH exome AF: 0.00408

GnomAD4 genome AF: 0.0104 AC: 1585 AN: 152328 Hom.: 29 Cov.: 33 AF XY: 0.0102 AC XY: 762 AN XY: 74482

Gnomad4 AFR AF: 0.0340

Gnomad4 AMR AF: 0.00516

Gnomad4 ASJ AF: 0.00662

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000632

Gnomad4 OTH AF: 0.00852

Alfa AF: 0.00289 Hom.: 12

Bravo AF: 0.0122

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.000873

EpiControl AF: 0.00107

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	11
DANN	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.012
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

Publications

LitVar

Other links and lift over

dbSNP: rs61755284; hg19: chr13-37012017;