rs1554063600

Variant names:

• chr5-75593902-A-G
• rs1554063600
• NM_016218.6:c.1381A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Moderate PP5_Moderate

The NM_016218.6(POLK):​c.1381A>G​(p.Lys461Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLK NM_016218.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.26
• Publications: 1 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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).
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.898
• PP5: Variant 5-75593902-A-G is Pathogenic according to our data. Variant chr5-75593902-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 218228.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLK	NM_016218.6	MANE Select	c.1381A>G	p.Lys461Glu	missense	Exon 12 of 15	NP_057302.1	Q9UBT6-1
	POLK	NM_001387111.3		c.1423A>G	p.Lys475Glu	missense	Exon 13 of 16	NP_001374040.1
	POLK	NM_001395894.1		c.1423A>G	p.Lys475Glu	missense	Exon 14 of 17	NP_001382823.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLK	ENST00000241436.9	TSL:1 MANE Select	c.1381A>G	p.Lys461Glu	missense	Exon 12 of 15	ENSP00000241436.4	Q9UBT6-1
	POLK	ENST00000508526.5	TSL:1	c.935-2320A>G		intron	N/A	ENSP00000426853.1	Q9UBT6-3
	POLK	ENST00000504026.5	TSL:1	c.1356+3462A>G		intron	N/A	ENSP00000425075.1	Q9UBT6-6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Prostate cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	28
DANN	Benign	0.91
DEOGEN2	Uncertain	0.58	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.054	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		9.3
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.86
MutPred		0.72		Loss of MoRF binding (P = 0.0056)
MVP		0.87
MPC		0.47
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.99
gMVP		0.87
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1554063600; hg19: chr5-74889727;