rs1554062741

Variant names:

• chr5-75590373-A-G
• rs1554062741
• ENST00000241436.9:c.1289A>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP2 PP5_Moderate

The ENST00000241436.9(POLK):​c.1289A>G​(p.Glu430Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLK ENST00000241436.9 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.02
• Publications: 1 publications found

Genes affected

POLK (HGNC:9183): (DNA polymerase kappa) This gene encodes a member of the DNA polymerase type-Y family of proteins. The encoded protein is a specialized DNA polymerase that catalyzes translesion DNA synthesis, which allows DNA replication in the presence of DNA lesions. Human cell lines lacking a functional copy of this gene exhibit impaired genome integrity and enhanced susceptibility to oxidative damage. Mutations in this gene that impair enzyme activity may be associated with prostate cancer in human patients. [provided by RefSeq, Sep 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 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 14 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.28752 (below the threshold of 3.09). Trascript score misZ: 0.94642 (below the threshold of 3.09).
• PP5: Variant 5-75590373-A-G is Pathogenic according to our data. Variant chr5-75590373-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 218219.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLK	NM_001387111.3	c.1331A>G	p.Glu444Gly	missense_variant	Exon 12 of 16		NP_001374040.1
POLK	NM_001395894.1	c.1331A>G	p.Glu444Gly	missense_variant	Exon 13 of 17		NP_001382823.1
POLK	NM_001395897.1	c.1328A>G	p.Glu443Gly	missense_variant	Exon 12 of 16		NP_001382826.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLK	ENST00000241436.9	c.1289A>G	p.Glu430Gly	missense_variant	Exon 11 of 15	1		ENSP00000241436.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Prostate cancer Pathogenic:1

Jun 10, 2013

Tulane Cancer Center, Tulane University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T;.;.
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.060	D
MetaRNN	Uncertain	0.53	D;D;D
MetaSVM	Benign	-0.43	T
MutationAssessor	Pathogenic	3.3	M;M;M
PhyloP100		9.0
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-4.2	D;D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0050	D;D;T
Sift4G	Benign	0.13	T;T;T
Polyphen		0.99	D;P;.
Vest4		0.56
MutPred		0.50		Loss of methylation at K427 (P = 0.0725);Loss of methylation at K427 (P = 0.0725);Loss of methylation at K427 (P = 0.0725);
MVP		0.68
MPC		0.22
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.84
gMVP		0.56
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs1554062741; hg19: chr5-74886198;