rs17349

Variant names:

• chr20-5118870-G-A
• rs17349
• NM_182649.2:c.222-4C>T

Your query was ambiguous. Multiple possible variants found:

• chr20-5118870-G-A
• chr20-5118870-G-C
• chr20-5118870-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_182649.2(PCNA):​c.222-4C>T variant causes a splice region, 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.15 (2422 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9461 hom.)
• Consequence: PCNA NM_182649.2 splice_region, intron
• Scores: Splicing: ADA: 0.000007966
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -1.17
• Publications: 25 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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -13 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 VariationId is 3060300.Status of the report is no_assertion_criteria_provided, 0 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 rank	MANE	Protein	UniProt
PCNA	NM_182649.2	c.222-4C>T		splice_region_variant, intron_variant	Intron 1 of 5	ENST00000379143.10	NP_872590.1
PCNA	NM_002592.2	c.222-4C>T		splice_region_variant, intron_variant	Intron 2 of 6		NP_002583.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCNA	ENST00000379143.10	c.222-4C>T		splice_region_variant, intron_variant	Intron 1 of 5	1	NM_182649.2	ENSP00000368438.5
PCNA	ENST00000379160.3	c.222-4C>T		splice_region_variant, intron_variant	Intron 2 of 6	5		ENSP00000368458.3

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

GnomAD2 exomes AF: 0.0982 AC: 24616 AN: 250734 AF XY: 0.0948

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 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

African (AFR) AF: 0.306 AC: 10084 AN: 32950

American (AMR) AF: 0.0706 AC: 3128 AN: 44330

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 3742 AN: 25944

East Asian (EAS) AF: 0.000127 AC: 5 AN: 39394

South Asian (SAS) AF: 0.0623 AC: 5331 AN: 85584

European-Finnish (FIN) AF: 0.0685 AC: 3655 AN: 53334

Middle Eastern (MID) AF: 0.155 AC: 887 AN: 5714

European-Non Finnish (NFE) AF: 0.110 AC: 120030 AN: 1088236

Other (OTH) AF: 0.115 AC: 6827 AN: 59308

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

African (AFR) AF: 0.295 AC: 12203 AN: 41420

American (AMR) AF: 0.108 AC: 1647 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 487 AN: 3472

East Asian (EAS) AF: 0.000773 AC: 4 AN: 5176

South Asian (SAS) AF: 0.0562 AC: 271 AN: 4822

European-Finnish (FIN) AF: 0.0595 AC: 630 AN: 10596

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.108 AC: 7317 AN: 67976

Other (OTH) AF: 0.150 AC: 316 AN: 2110

Alfa AF: 0.124 Hom.: 1542

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: no assertion criteria provided

Submissions by phenotype

PCNA-related disorder Benign:1

Oct 21, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17349; hg19: chr20-5099516; COSMIC: COSV104686840;