20-5117506-C-G

Variant names:

• chr20-5117506-C-G
• NM_182649.2:c.546G>C
• PCNA p.Leu182Phe

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_182649.2(PCNA):​c.546G>C​(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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L182W) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PCNA NM_182649.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.08
• Publications: 0 publications found

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]

PCNA Gene-Disease associations (from GenCC):

• ataxia-telangiectasia-like disorder 2

  Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• hereditary ataxia

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 2.4744 (below the threshold of 3.09). Trascript score misZ: 3.2291 (above the threshold of 3.09). GenCC associations: The gene is linked to hereditary ataxia, ataxia-telangiectasia-like disorder 2.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.84

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182649.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCNA	NM_182649.2	MANE Select	c.546G>C	p.Leu182Phe	missense	Exon 4 of 6	NP_872590.1	P12004
	PCNA	NM_002592.2		c.546G>C	p.Leu182Phe	missense	Exon 5 of 7	NP_002583.1	P12004

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCNA	ENST00000379143.10	TSL:1 MANE Select	c.546G>C	p.Leu182Phe	missense	Exon 4 of 6	ENSP00000368438.5	P12004
	PCNA	ENST00000379160.3	TSL:5	c.546G>C	p.Leu182Phe	missense	Exon 5 of 7	ENSP00000368458.3	P12004
	PCNA	ENST00000875657.1		c.546G>C	p.Leu182Phe	missense	Exon 5 of 7	ENSP00000545716.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.073	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	-0.027	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		1.1
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.037	D
Varity_R		0.94
gMVP		0.69
Mutation Taster		=14/86	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr20-5098152;