chr5-75596275-A-G

Variant names:

• chr5-75596275-A-G
• rs139591993
• NM_016218.6:c.1582A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM2 PM5 PP2 BP4

The NM_016218.6(POLK):​c.1582A>G​(p.Ser528Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S528C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLK NM_016218.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.37
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-75596275-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 218224.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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=0.36208445).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLK	NM_016218.6	c.1582A>G	p.Ser528Gly	missense_variant	Exon 13 of 15	ENST00000241436.9	NP_057302.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLK	ENST00000241436.9	c.1582A>G	p.Ser528Gly	missense_variant	Exon 13 of 15	1	NM_016218.6	ENSP00000241436.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 11, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1582A>G (p.S528G) alteration is located in exon 13 (coding exon 12) of the POLK gene. This alteration results from a A to G substitution at nucleotide position 1582, causing the serine (S) at amino acid position 528 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.36	T;T
MetaSVM	Uncertain	-0.088	T
PhyloP100		6.4
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.18
Sift	Uncertain	0.0020	D;T
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.16
MutPred		0.34		Loss of catalytic residue at S528 (P = 0.052);.;
MVP		0.89
MPC		0.074
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.35
gMVP		0.55
Mutation Taster		=23/77	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs139591993; hg19: chr5-74892100;