rs17349

chr20-5118870-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_182649.2(PCNA):c.222-4C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 1,586,834 control chromosomes in the GnomAD database, including 11,883 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.15 (2422 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9461 hom.)
• Consequence: PCNA NM_182649.2 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.000007966
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.17

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 20-5118870-G-A is Benign according to our data. Variant chr20-5118870-G-A is described in ClinVar as [Benign]. Clinvar id is 3060300.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.29 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCNA	NM_182649.2	c.222-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000379143.10
PCNA	NM_002592.2	c.222-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCNA	ENST00000379143.10	c.222-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_182649.2	P1
PCNA	ENST00000379160.3	c.222-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5		P1

Frequencies

GnomAD3 genomes AF: 0.151 AC: 23007 AN: 151922 Hom.: 2418 Cov.: 32

Gnomad AFR AF: 0.295

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.0559

Gnomad FIN AF: 0.0595

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.151

GnomAD3 exomes AF: 0.0982 AC: 24616 AN: 250734 Hom.: 1739 AF XY: 0.0948 AC XY: 12853 AN XY: 135556

Gnomad AFR exome AF: 0.300

Gnomad AMR exome AF: 0.0655

Gnomad ASJ exome AF: 0.135

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0580

Gnomad FIN exome AF: 0.0654

Gnomad NFE exome AF: 0.109

Gnomad OTH exome AF: 0.101

GnomAD4 exome AF: 0.107 AC: 153689 AN: 1434794 Hom.: 9461 Cov.: 27 AF XY: 0.105 AC XY: 75130 AN XY: 713208

Gnomad4 AFR exome AF: 0.306

Gnomad4 AMR exome AF: 0.0706

Gnomad4 ASJ exome AF: 0.144

Gnomad4 EAS exome AF: 0.000127

Gnomad4 SAS exome AF: 0.0623

Gnomad4 FIN exome AF: 0.0685

Gnomad4 NFE exome AF: 0.110

Gnomad4 OTH exome AF: 0.115

GnomAD4 genome AF: 0.152 AC: 23036 AN: 152040 Hom.: 2422 Cov.: 32 AF XY: 0.148 AC XY: 11006 AN XY: 74352

Gnomad4 AFR AF: 0.295

Gnomad4 AMR AF: 0.108

Gnomad4 ASJ AF: 0.140

Gnomad4 EAS AF: 0.000773

Gnomad4 SAS AF: 0.0562

Gnomad4 FIN AF: 0.0595

Gnomad4 NFE AF: 0.108

Gnomad4 OTH AF: 0.150

Alfa AF: 0.122 Hom.: 1243

Bravo AF: 0.161

Asia WGS AF: 0.0440 AC: 155 AN: 3478

EpiCase AF: 0.114

EpiControl AF: 0.117

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

PCNA-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	7.5
Dann	Benign	0.92

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000080
dbscSNV1_RF	Benign	0.0
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: rs17349; hg19: chr20-5099516; COSMIC: COSV104686840; COSMIC: COSV104686840;