rs2075784

Positions:

chr12-132687239-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006231.4(POLE):c.62+15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.516 in 1,472,344 control chromosomes in the GnomAD database, including 201,346 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.44 ( 15762 hom., cov: 31)

Exomes 𝑓: 0.53 ( 185584 hom. )

Consequence

POLE
NM_006231.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.624

Variant links:

Genes affected

POLE (HGNC:9177): (DNA polymerase epsilon, catalytic subunit) This gene encodes the catalytic subunit of DNA polymerase epsilon. The enzyme is involved in DNA repair and chromosomal DNA replication. Mutations in this gene have been associated with colorectal cancer 12 and facial dysmorphism, immunodeficiency, livedo, and short stature. [provided by RefSeq, Sep 2013]

POLE links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 12-132687239-G-A is Benign according to our data. Variant chr12-132687239-G-A is described in ClinVar as [Benign]. Clinvar id is 380208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132687239-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.535 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLE	NM_006231.4 linkuse as main transcript	c.62+15C>T		intron_variant		ENST00000320574.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLE	ENST00000320574.10 linkuse as main transcript	c.62+15C>T		intron_variant		1	NM_006231.4	P1

Frequencies

GnomAD3 genomes

AF:

0.437

AC:

66009

AN:

150952

Hom.:

15756

Cov.:

show subpopulations

Gnomad AFR

AF:

0.249

Gnomad AMI

AF:

0.660

Gnomad AMR

AF:

0.423

Gnomad ASJ

AF:

0.607

Gnomad EAS

AF:

0.295

Gnomad SAS

AF:

0.438

Gnomad FIN

AF:

0.529

Gnomad MID

AF:

0.484

Gnomad NFE

AF:

0.539

Gnomad OTH

AF:

0.448

GnomAD3 exomes

AF:

0.479

AC:

45218

AN:

94332

Hom.:

11313

AF XY:

0.486

AC XY:

25752

AN XY:

53040

show subpopulations

Gnomad AFR exome

AF:

0.247

Gnomad AMR exome

AF:

0.409

Gnomad ASJ exome

AF:

0.600

Gnomad EAS exome

AF:

0.288

Gnomad SAS exome

AF:

0.446

Gnomad FIN exome

AF:

0.542

Gnomad NFE exome

AF:

0.541

Gnomad OTH exome

AF:

0.499

GnomAD4 exome

AF:

0.525

AC:

694291

AN:

1321288

Hom.:

185584

Cov.:

AF XY:

0.523

AC XY:

341223

AN XY:

652046

show subpopulations

Gnomad4 AFR exome

AF:

0.245

Gnomad4 AMR exome

AF:

0.417

Gnomad4 ASJ exome

AF:

0.597

Gnomad4 EAS exome

AF:

0.303

Gnomad4 SAS exome

AF:

0.450

Gnomad4 FIN exome

AF:

0.538

Gnomad4 NFE exome

AF:

0.547

Gnomad4 OTH exome

AF:

0.510

GnomAD4 genome

AF:

0.437

AC:

66022

AN:

151056

Hom.:

15762

Cov.:

AF XY:

0.435

AC XY:

32081

AN XY:

73780

show subpopulations

Gnomad4 AFR

AF:

0.249

Gnomad4 AMR

AF:

0.423

Gnomad4 ASJ

AF:

0.607

Gnomad4 EAS

AF:

0.295

Gnomad4 SAS

AF:

0.439

Gnomad4 FIN

AF:

0.529

Gnomad4 NFE

AF:

0.539

Gnomad4 OTH

AF:

0.445

Alfa

AF:

0.495

Hom.:

3420

Bravo

AF:

0.423

Asia WGS

AF:

0.403

AC:

1398

AN:

3460

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 03, 2016	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 24, 2016	Variant summary: The POLE c.62+15C>T intronic variant involves the alteration of a non-conserved nucleotide. One in silico tool predicts a benign outcome for this variant along with 5/5 splice site tools predicitng the variant not to have an impact on splicing. This variant was found in 5171/10550 control chromosomes (1292 homozygotes) at a frequency of 0.4901422, which greatly exceeds the estimated maximal expected allele frequency of a pathogenic POLE variant (0.0000142), suggesting this variant is likely a benign polymorphism. Taken together, this variant is classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -

Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Colorectal cancer, susceptibility to, 12

Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 19, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Facial dysmorphism-immunodeficiency-livedo-short stature syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

DANN

Benign

0.88

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over