chr12-132639181-A-G

Position:

chr12-132639181-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_006231.4(POLE):c.5496T>C(p.Leu1832Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000439 in 1,614,112 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00045 ( 2 hom. )

Consequence

POLE
NM_006231.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -2.05

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 12-132639181-A-G is Benign according to our data. Variant chr12-132639181-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 240560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.05 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000447 (653/1461872) while in subpopulation EAS AF= 0.00474 (188/39700). AF 95% confidence interval is 0.00418. There are 2 homozygotes in gnomad4_exome. There are 321 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLE	NM_006231.4 linkuse as main transcript	c.5496T>C	p.Leu1832Leu	synonymous_variant	40/49	ENST00000320574.10	NP_006222.2	Q07864
POLE	XM_011534795.4 linkuse as main transcript	c.5496T>C	p.Leu1832Leu	synonymous_variant	40/48		XP_011533097.1
POLE	XM_011534797.4 linkuse as main transcript	c.4575T>C	p.Leu1525Leu	synonymous_variant	32/40		XP_011533099.1
POLE	XM_011534802.4 linkuse as main transcript	c.2484T>C	p.Leu828Leu	synonymous_variant	16/24		XP_011533104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10 linkuse as main transcript	c.5496T>C	p.Leu1832Leu	synonymous_variant	40/49	1	NM_006231.4	ENSP00000322570.5		Q07864

Frequencies

GnomAD3 genomes

AF:

0.000368

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000680

AC:

171

AN:

251444

Hom.:

AF XY:

0.000655

AC XY:

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00417

Gnomad EAS exome

AF:

0.00158

Gnomad SAS exome

AF:

0.000980

Gnomad FIN exome

AF:

0.000924

Gnomad NFE exome

AF:

0.000396

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.000447

AC:

653

AN:

1461872

Hom.:

Cov.:

AF XY:

0.000441

AC XY:

321

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00413

Gnomad4 EAS exome

AF:

0.00474

Gnomad4 SAS exome

AF:

0.000730

Gnomad4 FIN exome

AF:

0.000899

Gnomad4 NFE exome

AF:

0.000190

Gnomad4 OTH exome

AF:

0.000563

GnomAD4 genome

AF:

0.000368

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.000363

AC XY:

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00432

Gnomad4 EAS

AF:

0.00135

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.000942

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000568

Hom.:

Bravo

AF:

0.000276

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely 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	Aug 10, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 16, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 21, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 17, 2023	- -

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 11, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	POLE: BP4, BP7 -

Hereditary cancer-predisposing syndrome

Benign:3

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 23, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 28, 2015	This alteration is classified as likely 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. -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Oct 04, 2018	- -

Carcinoma of colon

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The POLE p.Leu1832= variant was not identified in the literature nor was it identified in the Cosmic database. The variant was identified in dbSNP (ID: rs147543146) as "With Likely benign allele", and in ClinVar (classified as benign by Invitae; as likely benign by GeneDx, Ambry Genetics, and one other clinical laboratory). The variant was identified in control databases in 167 of 277186 chromosomes (1 homozygous) at a frequency of 0.0006 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 2 of 6466 chromosomes (freq: 0.0003), European in 43 of 126684 chromosomes (freq: 0.0003), Ashkenazi Jewish in 40 of 10152 chromosomes (1 homozygous, freq: 0.0039), East Asian in 27 of 18870 chromosomes (freq: 0.0014), Finnish in 25 of 25790 chromosomes (freq: 0.001), and South Asian in 30 of 30782 chromosomes (freq: 0.00097), while the variant was not observed in the African or Latino populations. The p.Leu1832= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.22

DANN

Benign

0.34

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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