20-5119641-C-T

Position:

• chr20-5119641-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_182649.2(PCNA):​c.158G>A​(p.Arg53Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,410 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PCNA NM_182649.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.45

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-AS1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCNA	NM_182649.2	c.158G>A	p.Arg53Gln	missense_variant	1/6	ENST00000379143.10	NP_872590.1
PCNA	NM_002592.2	c.158G>A	p.Arg53Gln	missense_variant	2/7		NP_002583.1
PCNA-AS1	NR_028370.1	n.56C>T		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCNA	ENST00000379143.10	c.158G>A	p.Arg53Gln	missense_variant	1/6	1	NM_182649.2	ENSP00000368438.5
PCNA	ENST00000379160.3	c.158G>A	p.Arg53Gln	missense_variant	2/7	5		ENSP00000368458.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461410 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726950

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Jul 14, 2024

The c.158G>A (p.R53Q) alteration is located in exon 2 (coding exon 1) of the PCNA gene. This alteration results from a G to A substitution at nucleotide position 158, causing the arginine (R) at amino acid position 53 to be replaced by a glutamine (Q). 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	0.32
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.43	T;T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	.;D
M_CAP	Benign	0.042	D
MetaRNN	Uncertain	0.73	D;D
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	1.8	L;L
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Benign	0.15
Sift	Benign	0.034	D;D
Sift4G	Benign	0.11	T;T
Polyphen		0.68	P;P
Vest4		0.78
MutPred		0.47		Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);
MVP		0.56
MPC		1.3
ClinPred		0.99	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.62

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: rs2090503412; hg19: chr20-5100287;