rs770984846

Variant names:

• chr5-75590368-G-A
• rs770984846
• NM_016218.6:c.1284G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-75590368-G-A
• chr5-75590368-G-C
• chr5-75590368-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PP5_Moderate BP4 BP7

The NM_016218.6(POLK):​c.1284G>A​(p.Ala428Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000207 in 1,596,492 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: POLK NM_016218.6 synonymous
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.79
• Publications: 6 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 0 ACMG points.

• PP5: Variant 5-75590368-G-A is Pathogenic according to our data. Variant chr5-75590368-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 218217.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32). . Strength limited to SUPPORTING due to the PP5.
• BP7: Synonymous conserved (PhyloP=1.79 with no splicing effect.

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.1284G>A	p.Ala428Ala	synonymous	Exon 11 of 15	NP_057302.1	Q9UBT6-1
	POLK	NM_001387111.3		c.1326G>A	p.Ala442Ala	synonymous	Exon 12 of 16	NP_001374040.1
	POLK	NM_001395894.1		c.1326G>A	p.Ala442Ala	synonymous	Exon 13 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.1284G>A	p.Ala428Ala	synonymous	Exon 11 of 15	ENSP00000241436.4	Q9UBT6-1
	POLK	ENST00000515295.5	TSL:1	c.1284G>A	p.Ala428Ala	synonymous	Exon 10 of 10	ENSP00000424174.1	Q9UBT6-2
	POLK	ENST00000504026.5	TSL:1	c.1284G>A	p.Ala428Ala	synonymous	Exon 10 of 12	ENSP00000425075.1	Q9UBT6-6

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152106 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000243 AC: 6 AN: 246956 AF XY: 0.0000299

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000891

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000215 AC: 31 AN: 1444386 Hom.: 0 Cov.: 27 AF XY: 0.0000209 AC XY: 15 AN XY: 718696

African (AFR) AF: 0.0000303 AC: 1 AN: 32978

American (AMR) AF: 0.00 AC: 0 AN: 43266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25598

East Asian (EAS) AF: 0.00 AC: 0 AN: 39498

South Asian (SAS) AF: 0.000179 AC: 15 AN: 83972

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52808

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 0.00000908 AC: 10 AN: 1100984

Other (OTH) AF: 0.0000839 AC: 5 AN: 59592

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152106 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74284

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

African (AFR) AF: 0.0000242 AC: 1 AN: 41406

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.0000189

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
BayesDel_noAF	Benign	-0.32
CADD	Benign	13
DANN	Benign	0.59
PhyloP100		1.8
Mutation Taster		=99/1	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs770984846; hg19: chr5-74886193; COSMIC: COSV54034895;