5-75590351-A-C

Variant names:

• chr5-75590351-A-C
• rs35257416
• ENST00000241436.9:c.1267A>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PVS1_Moderate BS1 BS2

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.73

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: Likely_benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

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

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

Gnomad4 AFR exome AF: 0.0159 AC: 512 AN: 32270

Gnomad4 AMR exome AF: 0.00110 AC: 45 AN: 41086

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25000

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39368

Gnomad4 SAS exome AF: 0.000135 AC: 11 AN: 81766

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 52448

Gnomad4 NFE exome AF: 0.0000111 AC: 12 AN: 1084860

Gnomad4 Remaining exome 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

Gnomad4 AFR AF: 0.0162 AC: 0.0162385 AN: 0.0162385

Gnomad4 AMR AF: 0.00137 AC: 0.00137237 AN: 0.00137237

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000588 AC: 0.0000588114 AN: 0.0000588114

Gnomad4 OTH AF: 0.00379 AC: 0.00378788 AN: 0.00378788

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 v4.3

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
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

Publications

LitVar

Other links and lift over

dbSNP: rs35257416; hg19: chr5-74886176;