rs3822587

Positions:

• chr5-75596527-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001387111.3(POLK):​c.1876A>G​(p.Ile626Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000933 in 1,614,018 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00081 (9 hom.)
• Consequence: POLK NM_001387111.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.313

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002148807).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00208 (317/152344) while in subpopulation EAS AF= 0.0274 (142/5186). AF 95% confidence interval is 0.0237. There are 1 homozygotes in gnomad4. There are 148 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLK	NM_001387111.3	c.1876A>G	p.Ile626Val	missense_variant	14/16		NP_001374040.1
POLK	NM_001395894.1	c.1876A>G	p.Ile626Val	missense_variant	15/17		NP_001382823.1
POLK	NM_001395897.1	c.1873A>G	p.Ile625Val	missense_variant	14/16		NP_001382826.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLK	ENST00000241436.9	c.1834A>G	p.Ile612Val	missense_variant	13/15	1		ENSP00000241436.4

Frequencies

GnomAD3 genomes AF: 0.00208 AC: 317 AN: 152224 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00367

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0273

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00253 AC: 632 AN: 249636 Hom.: 9 AF XY: 0.00226 AC XY: 305 AN XY: 135254

Gnomad AFR exome AF: 0.00373

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0292

Gnomad SAS exome AF: 0.000687

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.000824

GnomAD4 exome AF: 0.000813 AC: 1189 AN: 1461674 Hom.: 9 Cov.: 32 AF XY: 0.000785 AC XY: 571 AN XY: 727142

Gnomad4 AFR exome AF: 0.00418

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0199

Gnomad4 SAS exome AF: 0.000800

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.00255

GnomAD4 genome AF: 0.00208 AC: 317 AN: 152344 Hom.: 1 Cov.: 32 AF XY: 0.00199 AC XY: 148 AN XY: 74508

Gnomad4 AFR AF: 0.00365

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0274

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000891 Hom.: 2

Bravo AF: 0.00237

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00240 AC: 291

Asia WGS AF: 0.0120 AC: 42 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	7.5
DANN	Uncertain	0.98
DEOGEN2	Benign	0.026	T;.
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.78
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.44	T;T
MetaRNN	Benign	0.0021	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.17	N;N
REVEL	Benign	0.027
Sift	Benign	1.0	T;D
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.053
MVP		0.34
MPC		0.060
ClinPred		0.0075	T
GERP RS		3.0
Varity_R		0.020
gMVP		0.094

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: rs3822587; hg19: chr5-74892352;