rs1554064175

Positions:

• chr5-75596345-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_001387111.3(POLK):​c.1694A>T​(p.Asp565Val) 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 benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLK NM_001387111.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.21

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]

POLK (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-75596345-A-T is Pathogenic according to our data. Variant chr5-75596345-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 218225.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.26270145). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLK	NM_001387111.3	c.1694A>T	p.Asp565Val	missense_variant	14/16		NP_001374040.1
POLK	NM_001395894.1	c.1694A>T	p.Asp565Val	missense_variant	15/17		NP_001382823.1
POLK	NM_001395897.1	c.1691A>T	p.Asp564Val	missense_variant	14/16		NP_001382826.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLK	ENST00000241436.9	c.1652A>T	p.Asp551Val	missense_variant	13/15	1		ENSP00000241436.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Feb 04, 2014

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T;.
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.85	D;D
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.3	M;.
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.8	D;N
REVEL	Benign	0.090
Sift	Uncertain	0.011	D;D
Sift4G	Uncertain	0.057	T;D
Polyphen		0.68	P;P
Vest4		0.34
MutPred		0.48		Gain of loop (P = 0.024);.;
MVP		0.76
MPC		0.15
ClinPred		0.62	D
GERP RS		3.2
Varity_R		0.13
gMVP		0.41

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554064175; hg19: chr5-74892170;