chr5-75590351-A-C

Variant names:

• chr5-75590351-A-C
• rs35257416
• NM_016218.6:c.1267A>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 3P and 12B. PM1 PP2 BP4_Strong BS1 BS2

The NM_016218.6(POLK):​c.1267A>C​(p.Ser423Arg) variant causes a missense 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. 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_016218.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.73
• Publications: 7 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_016218.6
• 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).
• BP4: Computational evidence support a benign effect (MetaRNN=0.009204656).
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLK	NM_016218.6	MANE Select	c.1267A>C	p.Ser423Arg	missense	Exon 11 of 15	NP_057302.1
	POLK	NM_001387111.3		c.1309A>C	p.Ser437Arg	missense	Exon 12 of 16	NP_001374040.1
	POLK	NM_001395894.1		c.1309A>C	p.Ser437Arg	missense	Exon 13 of 17	NP_001382823.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLK	ENST00000241436.9	TSL:1 MANE Select	c.1267A>C	p.Ser423Arg	missense	Exon 11 of 15	ENSP00000241436.4
	POLK	ENST00000515295.5	TSL:1	c.1267A>C	p.Ser423Arg	missense	Exon 10 of 10	ENSP00000424174.1
	POLK	ENST00000504026.5	TSL:1	c.1267A>C	p.Ser423Arg	missense	Exon 10 of 12	ENSP00000425075.1

Frequencies

GnomAD3 genomes AF: 0.00465 AC: 707 AN: 152198 Hom.: 5 Cov.: 32

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

GnomAD2 exomes AF: 0.00130 AC: 312 AN: 239804 AF XY: 0.000877

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 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

African (AFR) AF: 0.0159 AC: 512 AN: 32270

American (AMR) AF: 0.00110 AC: 45 AN: 41086

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25000

East Asian (EAS) AF: 0.00 AC: 0 AN: 39368

South Asian (SAS) AF: 0.000135 AC: 11 AN: 81766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52448

Middle Eastern (MID) AF: 0.00142 AC: 8 AN: 5618

European-Non Finnish (NFE) AF: 0.0000111 AC: 12 AN: 1084860

Other (OTH) AF: 0.00124 AC: 73 AN: 58670

GnomAD4 genome AF: 0.00465 AC: 708 AN: 152316 Hom.: 5 Cov.: 32 AF XY: 0.00431 AC XY: 321 AN XY: 74486

African (AFR) AF: 0.0162 AC: 675 AN: 41568

American (AMR) AF: 0.00137 AC: 21 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68014

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00251 Hom.: 11

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 v4.9

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
MetaRNN	Benign	0.0092	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		5.7
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.058
Sift	Benign	0.040	D
Sift4G	Benign	0.19	T
Polyphen		0.93	P
Vest4		0.47
MutPred		0.16		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
Mutation Taster		=78/22	polymorphism

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

Other links and lift over

dbSNP: rs35257416; hg19: chr5-74886176;