Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM2PP2PP5_ModerateBP4

The NM_016218.6(POLK):c.2033C>T(p.Ser678Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,398 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S678A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

POLK
NM_016218.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 0.879

Publications

4 publications found

Variant links:

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 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 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 5-75596726-C-T is Pathogenic according to our data. Variant chr5-75596726-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 218222.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.05650872). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016218.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
POLK	NM_016218.6	MANE Select	c.2033C>T	p.Ser678Phe	missense	Exon 13 of 15	NP_057302.1
POLK	NM_001387111.3		c.2075C>T	p.Ser692Phe	missense	Exon 14 of 16	NP_001374040.1
POLK	NM_001395894.1		c.2075C>T	p.Ser692Phe	missense	Exon 15 of 17	NP_001382823.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
POLK	ENST00000241436.9	TSL:1 MANE Select	c.2033C>T	p.Ser678Phe	missense	Exon 13 of 15	ENSP00000241436.4
POLK	ENST00000508526.5	TSL:1	c.1439C>T	p.Ser480Phe	missense	Exon 7 of 9	ENSP00000426853.1
POLK	ENST00000514141.5	TSL:1	n.*652C>T		non_coding_transcript_exon	Exon 11 of 13	ENSP00000423526.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461398

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726988

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33468

American (AMR)

AF:

0.00

AC:

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.00

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53184

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111872

Other (OTH)

AF:

0.00

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Prostate cancer (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.63

CADD

Benign

6.5

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.039

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0045

LIST_S2

Benign

0.65

M_CAP

Benign

0.0084

MetaRNN

Benign

0.057

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.3

PhyloP100

0.88

PrimateAI

Benign

0.20

PROVEAN

Benign

-0.90

REVEL

Benign

0.058

Sift

Benign

0.69

Sift4G

Benign

0.13

Polyphen

0.0010

Vest4

0.084

MutPred

0.33

Loss of disorder (P = 0.0012)

MVP

0.41

MPC

0.076

ClinPred

0.68

GERP RS

1.3

Varity_R

0.025

gMVP

0.15

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

NM_016218.6:c.2033C>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over