Genetic Variant POLK:p.Ser423Arg (chr5-75590351-A-C) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PVS1_ModerateBS1BS2

The NM_001387110.3(POLK):c.1260-2A>C variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00087 in 1,573,402 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0046 ( 5 hom., cov: 32)

Exomes 𝑓: 0.00047 ( 9 hom. )

Consequence

POLK
NM_001387110.3 splice_acceptor, intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.73

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 made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.033794165 fraction of the gene. Cryptic splice site detected, with MaxEntScore 11, offset of -9, new splice context is: aattattcttgtctttctAGgac. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00465 (708/152316) while in subpopulation AFR AF= 0.0162 (675/41568). AF 95% confidence interval is 0.0152. There are 5 homozygotes in gnomad4. There are 321 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein
POLK	NM_001387111.3 link	c.1309A>C	p.Ser437Arg	missense_variant	Exon 12 of 16	NP_001374040.1
POLK	NM_001395894.1 link	c.1309A>C	p.Ser437Arg	missense_variant	Exon 13 of 17	NP_001382823.1
POLK	NM_001395897.1 link	c.1306A>C	p.Ser436Arg	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 link	c.1267A>C	p.Ser423Arg	missense_variant	Exon 11 of 15	1		ENSP00000241436.4		Q9UBT6-1

Frequencies

GnomAD3 genomes

AF:

0.00465

AC:

707

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0163

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00383

GnomAD3 exomes

AF:

0.00130

AC:

312

AN:

239804

Hom.:

AF XY:

0.000877

AC XY:

114

AN XY:

129936

show subpopulations

Gnomad AFR exome

AF:

0.0173

Gnomad AMR exome

AF:

0.000900

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000701

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000182

Gnomad OTH exome

AF:

0.000518

GnomAD4 exome

AF:

0.000465

AC:

661

AN:

1421086

Hom.:

Cov.:

AF XY:

0.000417

AC XY:

295

AN XY:

707390

show subpopulations

Gnomad4 AFR exome

AF:

0.0159

Gnomad4 AMR exome

AF:

0.00110

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000135

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000111

Gnomad4 OTH exome

AF:

0.00124

GnomAD4 genome

AF:

0.00465

AC:

708

AN:

152316

Hom.:

Cov.:

AF XY:

0.00431

AC XY:

321

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.0162

Gnomad4 AMR

AF:

0.00137

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.00168

Hom.:

Bravo

AF:

0.00553

ESP6500AA

AF:

0.0186

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00174

AC:

211

Asia WGS

AF:

0.00145

AC:

AN:

3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

T;.;.

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

D;D;D

MetaRNN

Benign

0.0092

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

L;L;L

PrimateAI

Benign

0.38

PROVEAN

Benign

-2.3

N;N;N

REVEL

Benign

0.058

Sift

Benign

0.040

D;T;T

Sift4G

Benign

0.19

T;T;T

Polyphen

0.93

P;P;.

Vest4

0.47

MutPred

0.16

Loss of phosphorylation at S423 (P = 0.0313);Loss of phosphorylation at S423 (P = 0.0313);Loss of phosphorylation at S423 (P = 0.0313);

MVP

0.51

MPC

0.15

ClinPred

0.028

GERP RS

5.4

Varity_R

0.35

gMVP

0.27

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over