12-132676210-C-G

Position:

chr12-132676210-C-G

Variant summary

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

The NM_006231.4(POLE):c.910-6G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.675 in 1,600,780 control chromosomes in the GnomAD database, including 369,890 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.65 ( 32628 hom., cov: 34)

Exomes 𝑓: 0.68 ( 337262 hom. )

Consequence

POLE
NM_006231.4 splice_region, intron

Scores

Splicing: ADA: 0.00006661

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14O:1

Conservation

PhyloP100: -0.0250

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:

POLE (HGNC:):

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=-0.83).

BP6

Variant 12-132676210-C-G is Benign according to our data. Variant chr12-132676210-C-G is described in ClinVar as [Benign]. Clinvar id is 380209.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132676210-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.695 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLE	NM_006231.4 linkuse as main transcript	c.910-6G>C		splice_region_variant, intron_variant		ENST00000320574.10	NP_006222.2	Q07864

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10 linkuse as main transcript	c.910-6G>C		splice_region_variant, intron_variant		1	NM_006231.4	ENSP00000322570.5		Q07864

Frequencies

GnomAD3 genomes

AF:

0.649

AC:

98692

AN:

152056

Hom.:

32585

Cov.:

show subpopulations

Gnomad AFR

AF:

0.634

Gnomad AMI

AF:

0.767

Gnomad AMR

AF:

0.588

Gnomad ASJ

AF:

0.779

Gnomad EAS

AF:

0.308

Gnomad SAS

AF:

0.600

Gnomad FIN

AF:

0.601

Gnomad MID

AF:

0.652

Gnomad NFE

AF:

0.700

Gnomad OTH

AF:

0.660

GnomAD3 exomes

AF:

0.623

AC:

155218

AN:

249280

Hom.:

50124

AF XY:

0.629

AC XY:

84879

AN XY:

134870

show subpopulations

Gnomad AFR exome

AF:

0.635

Gnomad AMR exome

AF:

0.509

Gnomad ASJ exome

AF:

0.769

Gnomad EAS exome

AF:

0.303

Gnomad SAS exome

AF:

0.603

Gnomad FIN exome

AF:

0.609

Gnomad NFE exome

AF:

0.700

Gnomad OTH exome

AF:

0.665

GnomAD4 exome

AF:

0.678

AC:

981617

AN:

1448606

Hom.:

337262

Cov.:

AF XY:

0.676

AC XY:

487560

AN XY:

721476

show subpopulations

Gnomad4 AFR exome

AF:

0.641

Gnomad4 AMR exome

AF:

0.523

Gnomad4 ASJ exome

AF:

0.771

Gnomad4 EAS exome

AF:

0.307

Gnomad4 SAS exome

AF:

0.603

Gnomad4 FIN exome

AF:

0.615

Gnomad4 NFE exome

AF:

0.705

Gnomad4 OTH exome

AF:

0.678

GnomAD4 genome

AF:

0.649

AC:

98782

AN:

152174

Hom.:

32628

Cov.:

AF XY:

0.641

AC XY:

47685

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.635

Gnomad4 AMR

AF:

0.587

Gnomad4 ASJ

AF:

0.779

Gnomad4 EAS

AF:

0.307

Gnomad4 SAS

AF:

0.601

Gnomad4 FIN

AF:

0.601

Gnomad4 NFE

AF:

0.700

Gnomad4 OTH

AF:

0.657

Alfa

AF:

0.674

Hom.:

9083

Bravo

AF:

0.646

Asia WGS

AF:

0.518

AC:

1805

AN:

3478

EpiCase

AF:

0.714

EpiControl

AF:

0.713

ClinVar

Significance: Benign

Submissions summary: Benign:14Other:1

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, 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	Oct 29, 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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:4Other:1

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 25, 2016	Variant summary: The POLE c.910-6G>C 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 predicting the variant to to have an impact on normal splicing. This variant was found in 76218/120852 control chromosomes (24815 homozygotes) at a frequency of 0.6306722 suggesting the variant to be the ancestral allele and a benign polymorphism. Taken together, this variant is classified as Benign. -

Colorectal cancer, susceptibility to, 12

Benign:2

Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Dec 19, 2024	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 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

- -

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

-0.83

CADD

Benign

0.86

DANN

Benign

0.59

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000067

dbscSNV1_RF

Benign

0.018

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