Genetic Variant POLK:c.-14+678G>A (chr5-75512592-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_016218.6(POLK):c.-14+678G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0991 in 152,218 control chromosomes in the GnomAD database, including 890 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.099 ( 890 hom., cov: 32)

Exomes 𝑓: 0.17 ( 0 hom. )

Consequence

POLK
NM_016218.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.141

Publications

11 publications found

Variant links:

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]

POLK links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.194 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
POLK	NM_016218.6	MANE Select	c.-14+678G>A	intron	N/A	NP_057302.1	Q9UBT6-1
POLK	NM_001387111.3		c.-14+678G>A	intron	N/A	NP_001374040.1
POLK	NM_001395894.1		c.-151+678G>A	intron	N/A	NP_001382823.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
POLK	ENST00000241436.9	TSL:1 MANE Select	c.-14+678G>A	intron	N/A	ENSP00000241436.4	Q9UBT6-1
POLK	ENST00000514296.5	TSL:5	c.-505G>A	5_prime_UTR	Exon 1 of 6	ENSP00000425208.1	D6RDX9
POLK	ENST00000863893.1		c.-151+678G>A	intron	N/A	ENSP00000533952.1

Frequencies

GnomAD3 genomes

AF:

0.0992

AC:

15082

AN:

152094

Hom.:

890

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0466

Gnomad AMI

AF:

0.258

Gnomad AMR

AF:

0.0928

Gnomad ASJ

AF:

0.0894

Gnomad EAS

AF:

0.181

Gnomad SAS

AF:

0.205

Gnomad FIN

AF:

0.138

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.111

Gnomad OTH

AF:

0.0924

GnomAD4 exome

AF:

0.167

AC:

AN:

Hom.:

Cov.:

AF XY:

0.250

AC XY:

AN XY:

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.500

AC:

AN:

Other (OTH)

AF:

0.00

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0991

AC:

15087

AN:

152212

Hom.:

890

Cov.:

AF XY:

0.102

AC XY:

7591

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.0467

AC:

1939

AN:

41548

American (AMR)

AF:

0.0928

AC:

1420

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0894

AC:

310

AN:

3466

East Asian (EAS)

AF:

0.182

AC:

941

AN:

5182

South Asian (SAS)

AF:

0.205

AC:

989

AN:

4822

European-Finnish (FIN)

AF:

0.138

AC:

1461

AN:

10586

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.111

AC:

7580

AN:

68006

Other (OTH)

AF:

0.0919

AC:

194

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

677

1353

2030

2706

3383

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

182

364

546

728

910

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.106

Hom.:

1491

Bravo

AF:

0.0905

Asia WGS

AF:

0.157

AC:

546

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

9.2

(source)

DANN

Benign

0.75

PhyloP100

0.14

PromoterAI

-0.0052

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over