ENST00000241436.9:c.145T>C

Variant names:

• chr5-75552481-T-C
• NM_016218.6:c.145T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The ENST00000241436.9(POLK):​c.145T>C​(p.Phe49Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLK ENST00000241436.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.72
• 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 3 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).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000241436.9. 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.145T>C	p.Phe49Leu	missense	Exon 3 of 15	NP_057302.1	Q9UBT6-1
	POLK	NM_001387111.3		c.145T>C	p.Phe49Leu	missense	Exon 3 of 16	NP_001374040.1
	POLK	NM_001395894.1		c.145T>C	p.Phe49Leu	missense	Exon 4 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.145T>C	p.Phe49Leu	missense	Exon 3 of 15	ENSP00000241436.4	Q9UBT6-1
	POLK	ENST00000508526.5	TSL:1	c.145T>C	p.Phe49Leu	missense	Exon 2 of 9	ENSP00000426853.1	Q9UBT6-3
	POLK	ENST00000515295.5	TSL:1	c.145T>C	p.Phe49Leu	missense	Exon 2 of 10	ENSP00000424174.1	Q9UBT6-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.057	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		7.7
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.70
MutPred		0.31		Gain of helix (P = 0.2059)
MVP		0.81
MPC		0.38
ClinPred		0.99	D
GERP RS		6.1
Varity_R		0.70
gMVP		0.42
Mutation Taster		=11/89	disease causing

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

hg19: chr5-74848306;