20-5119682-G-T

Variant names:

• chr20-5119682-G-T
• rs1050525
• NM_182649.2:c.117C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The NM_182649.2(PCNA):​c.117C>A​(p.Ser39Arg) 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.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PCNA NM_182649.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.65
• Publications: 6 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]

ENSG00000302261 (HGNC:):

PCNA-AS1 (HGNC:37184): (PCNA antisense RNA 1)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 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 ataxia-telangiectasia-like disorder 2.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.95

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCNA	NM_182649.2	c.117C>A	p.Ser39Arg	missense_variant	Exon 1 of 6	ENST00000379143.10	NP_872590.1
PCNA	NM_002592.2	c.117C>A	p.Ser39Arg	missense_variant	Exon 2 of 7		NP_002583.1
PCNA-AS1	NR_028370.1	n.97G>T		non_coding_transcript_exon_variant	Exon 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCNA	ENST00000379143.10	c.117C>A	p.Ser39Arg	missense_variant	Exon 1 of 6	1	NM_182649.2	ENSP00000368438.5
PCNA	ENST00000379160.3	c.117C>A	p.Ser39Arg	missense_variant	Exon 2 of 7	5		ENSP00000368458.3
ENSG00000302261	ENST00000785235.1	n.136G>T		non_coding_transcript_exon_variant	Exon 1 of 1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T;T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	.;D
M_CAP	Benign	0.081	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.2	M;M
PhyloP100		2.6
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.5	D;D
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.93	P;P
Vest4		0.84
MutPred		0.87		Loss of disorder (P = 0.0812);Loss of disorder (P = 0.0812);
MVP		0.91
MPC		2.1
ClinPred		0.96	D
GERP RS		2.8
PromoterAI		-0.00030	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.97
Mutation Taster		=19/81	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

Other links and lift over

dbSNP: rs1050525; hg19: chr20-5100328;