13-36437830-G-A

Position:

• chr13-36437830-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The ENST00000255465.8(CCNA1):​c.367G>A​(p.Gly123Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: CCNA1 ENST00000255465.8 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.61

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.040007234).
• BP6: Variant 13-36437830-G-A is Benign according to our data. Variant chr13-36437830-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2298100.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCNA1	NM_001413923.1	c.367G>A	p.Gly123Ser	missense_variant	3/9	ENST00000255465.8	NP_001400852.1
CCNA1	XM_011535294.3	c.367G>A	p.Gly123Ser	missense_variant	3/9		XP_011533596.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCNA1	ENST00000255465.8	c.367G>A	p.Gly123Ser	missense_variant	3/9	1	NM_001413923.1	ENSP00000255465	P1
CCNA1	ENST00000625767.2	c.367G>A	p.Gly123Ser	missense_variant	3/9	1		ENSP00000486017	P1
CCNA1	ENST00000440264.5	c.367G>A	p.Gly123Ser	missense_variant	3/9	2		ENSP00000400666	P1
CCNA1	ENST00000630422.2	c.367G>A	p.Gly123Ser	missense_variant	3/9	2		ENSP00000486482	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251338 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135844

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461682 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727150

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 28, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	10
DANN	Benign	0.46
DEOGEN2	Benign	0.056	.;.;T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.0061	N
LIST_S2	Benign	0.24	.;T;T;T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.040	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-2.5	.;.;N;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	1.2	.;N;N;.
REVEL	Benign	0.060
Sift	Benign	1.0	.;T;T;.
Sift4G	Benign	0.96	T;T;T;T
Polyphen		0.0	.;.;B;B
Vest4		0.095
MVP		0.43
MPC		0.39
ClinPred		0.0094	T
GERP RS		2.1
Varity_R		0.020
gMVP		0.14

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

LitVar

Other links and lift over

dbSNP: rs753604464; hg19: chr13-37011967; COSMIC: COSV55225295;