rs863225454

Variant names:

• chr5-75573739-C-T
• rs863225454
• NM_016218.6:c.410C>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP2 PP3 PP5

The ENST00000241436.9(POLK):​c.410C>T​(p.Ser137Phe) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLK ENST00000241436.9 missense, splice_region
• Scores: Splicing: ADA: 0.03488
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 5.01
• Publications: 3 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 5 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, 0.839
• PP5: Variant 5-75573739-C-T is Pathogenic according to our data. Variant chr5-75573739-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 218231.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLK	NM_016218.6	MANE Select	c.410C>T	p.Ser137Phe	missense splice_region	Exon 5 of 15	NP_057302.1
	POLK	NM_001395897.1		c.449C>T	p.Ser150Phe	missense	Exon 6 of 16	NP_001382826.1
	POLK	NM_001387111.3		c.410C>T	p.Ser137Phe	missense splice_region	Exon 5 of 16	NP_001374040.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLK	ENST00000241436.9	TSL:1 MANE Select	c.410C>T	p.Ser137Phe	missense splice_region	Exon 5 of 15	ENSP00000241436.4
	POLK	ENST00000508526.5	TSL:1	c.410C>T	p.Ser137Phe	missense splice_region	Exon 4 of 9	ENSP00000426853.1
	POLK	ENST00000515295.5	TSL:1	c.410C>T	p.Ser137Phe	missense splice_region	Exon 4 of 10	ENSP00000424174.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
1	-	-	Prostate cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.076	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		5.0
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.85
MutPred		0.70		Loss of disorder (P = 0.0022)
MVP		0.94
MPC		0.41
ClinPred		0.99	D
GERP RS		3.0
Varity_R		0.89
gMVP		0.78
Mutation Taster		=39/61	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.035
dbscSNV1_RF	Benign	0.32
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: rs863225454; hg19: chr5-74869564;