5-75590373-A-G

Position:

• chr5-75590373-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 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

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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-75590373-A-G is Pathogenic according to our data. Variant chr5-75590373-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 218219.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLK	NM_016218.6	c.1289A>G	p.Glu430Gly	missense_variant	11/15	ENST00000241436.9
POLK	NR_170560.3	n.1463A>G		non_coding_transcript_exon_variant	12/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLK	ENST00000241436.9	c.1289A>G	p.Glu430Gly	missense_variant	11/15	1	NM_016218.6	P1

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

Malignant tumor of prostate Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Tulane Cancer Center, Tulane University

Jun 10, 2013

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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
MutationTaster	Benign	1.0	D;D;D;D;D;D
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554062741; hg19: chr5-74886198;