chr4-121822594-G-A

Position:

• chr4-121822594-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001237.5(CCNA2):​c.266C>T​(p.Pro89Leu) variant causes a missense 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. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CCNA2 NM_001237.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.13

Genes affected

CCNA2 (HGNC:1578): (cyclin A2) The protein encoded by this gene belongs to the highly conserved cyclin family, whose members function as regulators of the cell cycle. This protein binds and activates cyclin-dependent kinase 2 and thus promotes transition through G1/S and G2/M. [provided by RefSeq, Aug 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0917041).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCNA2	NM_001237.5	c.266C>T	p.Pro89Leu	missense_variant	2/8	ENST00000274026.10	NP_001228.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCNA2	ENST00000274026.10	c.266C>T	p.Pro89Leu	missense_variant	2/8	1	NM_001237.5	ENSP00000274026.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 05, 2024

The c.266C>T (p.P89L) alteration is located in exon 2 (coding exon 2) of the CCNA2 gene. This alteration results from a C to T substitution at nucleotide position 266, causing the proline (P) at amino acid position 89 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	0.072
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.12	T;T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.0063
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.77	.;T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.092	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.75	N;.
REVEL	Benign	0.085
Sift	Benign	0.094	T;.
Sift4G	Benign	0.26	T;T
Polyphen		0.0020	B;B
Vest4		0.18
MutPred		0.34		Loss of catalytic residue at P88 (P = 0.0131);Loss of catalytic residue at P88 (P = 0.0131);
MVP		0.26
MPC		0.69
ClinPred		0.22	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.086
gMVP		0.22

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: rs1560633147; hg19: chr4-122743749;