5-75590351-A-C

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

1
4
13

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]

Genome browser will be placed here

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 MANE Protein UniProt
POLKNM_001387111.3 linkc.1309A>C p.Ser437Arg missense_variant Exon 12 of 16 NP_001374040.1
POLKNM_001395894.1 linkc.1309A>C p.Ser437Arg missense_variant Exon 13 of 17 NP_001382823.1
POLKNM_001395897.1 linkc.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
POLKENST00000241436.9 linkc.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.:
5
Cov.:
32
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.:
6
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.:
9
Cov.:
25
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.:
5
Cov.:
32
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.:
6
Bravo
AF:
0.00553
ESP6500AA
AF:
0.0186
AC:
82
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.00174
AC:
211
Asia WGS
AF:
0.00145
AC:
5
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
T
BayesDel_noAF
Benign
-0.34
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.18
T;.;.
Eigen
Uncertain
0.23
Eigen_PC
Uncertain
0.34
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.94
D;D;D
MetaRNN
Benign
0.0092
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.7
L;L;L
PrimateAI
Benign
0.38
T
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
T
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.

Other links and lift over

dbSNP: rs35257416; hg19: chr5-74886176; API