12-132632317-T-C

Position:

chr12-132632317-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_006231.4(POLE):c.6328A>G(p.Lys2110Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,613,362 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

POLE
NM_006231.4 missense, splice_region

Scores

Splicing: ADA: 0.005597

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 3.29

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 Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.20080227).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLE	NM_006231.4 linkuse as main transcript	c.6328A>G	p.Lys2110Glu	missense_variant, splice_region_variant	45/49	ENST00000320574.10	NP_006222.2	Q07864
POLE	XM_011534795.4 linkuse as main transcript	c.6328A>G	p.Lys2110Glu	missense_variant, splice_region_variant	45/48		XP_011533097.1
POLE	XM_011534797.4 linkuse as main transcript	c.5407A>G	p.Lys1803Glu	missense_variant, splice_region_variant	37/40		XP_011533099.1
POLE	XM_011534802.4 linkuse as main transcript	c.3316A>G	p.Lys1106Glu	missense_variant, splice_region_variant	21/24		XP_011533104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10 linkuse as main transcript	c.6328A>G	p.Lys2110Glu	missense_variant, splice_region_variant	45/49	1	NM_006231.4	ENSP00000322570.5		Q07864

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

250706

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

135540

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000442

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000198

AC:

AN:

1461174

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

726924

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000252

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 2110 of the POLE protein (p.Lys2110Glu). This variant is present in population databases (rs746736600, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with POLE-related conditions. ClinVar contains an entry for this variant (Variation ID: 240590). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 15, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 05, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 12, 2018	- -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2024

The c.6328A>G (p.K2110E) alteration is located in exon 45 (coding exon 45) of the POLE gene. This alteration results from a A to G substitution at nucleotide position 6328, causing the lysine (K) at amino acid position 2110 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.50

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

T;.

Eigen

Benign

-0.098

Eigen_PC

Benign

0.058

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.89

D;D

M_CAP

Benign

0.0033

MetaRNN

Benign

0.20

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.48

N;.

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.9

N;N

REVEL

Benign

0.094

Sift

Benign

0.18

T;T

Sift4G

Benign

0.25

T;T

Polyphen

0.0010

B;.

Vest4

0.27

MVP

0.33

MPC

0.27

ClinPred

0.22

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.15

gMVP

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0056

dbscSNV1_RF

Benign

0.22

SpliceAI score (max)

0.080

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