13-36433057-A-C

Variant names:

• chr13-36433057-A-C
• ENST00000255465.8:c.1A>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_Supporting PM2

The NM_001111045.4(CCNA1):​c.1A>C​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CCNA1 NM_001111045.4 initiator_codon
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.80

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 Uncertain_significance. Variant got 3 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 95 codons. Genomic position: 36437746. Lost 0.224 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCNA1	NM_001111045.4	c.1A>C	p.Met1?	initiator_codon_variant	Exon 2 of 9		NP_001104515.2
CCNA1	NM_001111046.2	c.1A>C	p.Met1?	initiator_codon_variant	Exon 2 of 9		NP_001104516.1
CCNA1	NM_001111047.2	c.1A>C	p.Met1?	initiator_codon_variant	Exon 2 of 9		NP_001104517.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCNA1	ENST00000255465.8	c.1A>C	p.Met1?	initiator_codon_variant	Exon 2 of 9	1		ENSP00000255465.5
CCNA1	ENST00000625767.2	c.1A>C	p.Met1?	initiator_codon_variant	Exon 2 of 9	1		ENSP00000486017.2
CCNA1	ENST00000440264.5	c.1A>C	p.Met1?	initiator_codon_variant	Exon 2 of 9	2		ENSP00000400666.1
CCNA1	ENST00000630422.2	c.1A>C	p.Met1?	initiator_codon_variant	Exon 2 of 9	2		ENSP00000486482.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.133A>C (p.M45L) alteration is located in exon 2 (coding exon 2) of the CCNA1 gene. This alteration results from a A to C substitution at nucleotide position 133, causing the methionine (M) at amino acid position 45 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	13
DANN	Benign	0.88
DEOGEN2	Benign	0.11	.;.;T;.
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.46	N
LIST_S2	Uncertain	0.90	.;D;T;T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.23	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	.;.;L;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.64	.;N;N;.
REVEL	Benign	0.13
Sift	Pathogenic	0.0	.;D;D;.
Sift4G	Pathogenic	0.0	D;D;T;T
Polyphen		0.12, 0.18	.;.;B;B
Vest4		0.64
MutPred		0.31		.;.;Loss of sheet (P = 0.0457);.;
MVP		0.57
MPC		0.45
ClinPred		0.75	D
GERP RS		2.1
Varity_R		0.10
gMVP		0.47

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-37007194;