5-75581364-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The ENST00000241436.9(POLK):c.850G>C(p.Val284Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. 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: 0.248

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a domain UmuC (size 255) in uniprot entity POLK_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in ENST00000241436.9
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.075387955).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLK	NM_016218.6	c.850G>C	p.Val284Leu	missense_variant	7/15	ENST00000241436.9
POLK	NR_170560.3	n.1024G>C		non_coding_transcript_exon_variant	8/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLK	ENST00000241436.9	c.850G>C	p.Val284Leu	missense_variant	7/15	1	NM_016218.6	P1

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 16, 2023

The c.850G>C (p.V284L) alteration is located in exon 7 (coding exon 6) of the POLK gene. This alteration results from a G to C substitution at nucleotide position 850, causing the valine (V) at amino acid position 284 to be replaced by a leucine (L). 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	0.14
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	18
Dann	Benign	0.85
DEOGEN2	Benign	0.23	T;.;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.31	N
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.075	T;T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	-0.12	N;N;N;N
MutationTaster	Benign	0.76	D;D;D;D;D;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.5	N;N;N;N
REVEL	Benign	0.16
Sift	Benign	0.11	T;T;T;D
Sift4G	Benign	0.082	T;D;T;T
Polyphen		0.34	B;B;.;B
Vest4		0.16
MutPred		0.55		Gain of catalytic residue at V284 (P = 0.0859);Gain of catalytic residue at V284 (P = 0.0859);Gain of catalytic residue at V284 (P = 0.0859);Gain of catalytic residue at V284 (P = 0.0859);
MVP		0.43
MPC		0.098
ClinPred		0.15	T
GERP RS		0.36
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-74877189;