rs369958038
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Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate
The NM_182649.2(PCNA):c.683G>T(p.Ser228Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
PCNA
NM_182649.2 missense
NM_182649.2 missense
Scores
9
7
3
Clinical Significance
Conservation
PhyloP100: 7.76
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 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, 0.9
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PCNA | NM_182649.2 | c.683G>T | p.Ser228Ile | missense_variant | 5/6 | ENST00000379143.10 | NP_872590.1 | |
PCNA | NM_002592.2 | c.683G>T | p.Ser228Ile | missense_variant | 6/7 | NP_002583.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PCNA | ENST00000379143.10 | c.683G>T | p.Ser228Ile | missense_variant | 5/6 | 1 | NM_182649.2 | ENSP00000368438.5 | ||
PCNA | ENST00000379160.3 | c.683G>T | p.Ser228Ile | missense_variant | 6/7 | 5 | ENSP00000368458.3 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152196Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251410Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135876
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GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461772Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727192
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152196Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74344
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Ataxia-telangiectasia-like disorder 2 Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Apr 03, 2018 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2014 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;M
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Benign
D;D
Sift4G
Benign
T;T
Polyphen
P;P
Vest4
MVP
MPC
1.9
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at