20-5117506-C-A

Position:

• chr20-5117506-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_182649.2(PCNA):​c.546G>T​(p.Leu182Phe) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PCNA NM_182649.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.08

Genes affected

PCNA (HGNC:8729): (proliferating cell nuclear antigen) The protein encoded by this gene is found in the nucleus and is a cofactor of DNA polymerase delta. The encoded protein acts as a homotrimer and helps increase the processivity of leading strand synthesis during DNA replication. In response to DNA damage, this protein is ubiquitinated and is involved in the RAD6-dependent DNA repair pathway. Two transcript variants encoding the same protein have been found for this gene. Pseudogenes of this gene have been described on chromosome 4 and on the X chromosome. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PCNA. . Gene score misZ 2.4744 (greater than the threshold 3.09). Trascript score misZ 3.2291 (greater than threshold 3.09). GenCC has associacion of gene with ataxia-telangiectasia-like disorder 2.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.839

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCNA	NM_182649.2	c.546G>T	p.Leu182Phe	missense_variant	4/6	ENST00000379143.10	NP_872590.1
PCNA	NM_002592.2	c.546G>T	p.Leu182Phe	missense_variant	5/7		NP_002583.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCNA	ENST00000379143.10	c.546G>T	p.Leu182Phe	missense_variant	4/6	1	NM_182649.2	ENSP00000368438.5
PCNA	ENST00000379160.3	c.546G>T	p.Leu182Phe	missense_variant	5/7	5		ENSP00000368458.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

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 02, 2023

The c.546G>T (p.L182F) alteration is located in exon 5 (coding exon 4) of the PCNA gene. This alteration results from a G to T substitution at nucleotide position 546, causing the leucine (L) at amino acid position 182 to be replaced by a phenylalanine (F). 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	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.64	D;D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.96	.;D
M_CAP	Benign	0.061	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Uncertain	-0.027	T
MutationAssessor	Uncertain	2.7	M;M
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.037	D;D
Polyphen		0.97	D;D
Vest4		0.75
MutPred		0.70		Loss of disorder (P = 0.1551);Loss of disorder (P = 0.1551);
MVP		0.72
MPC		2.3
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.94
gMVP		0.69

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: chr20-5098152;