Variant 12-132632332-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_006231.4(POLE):c.6313A>C(p.Ile2105Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I2105V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

POLE
NM_006231.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.01

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.31683177).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
POLE	NM_006231.4 linkuse as main transcript	c.6313A>C	p.Ile2105Leu	missense_variant	45/49	ENST00000320574.10
POLE	XM_011534795.4 linkuse as main transcript	c.6313A>C	p.Ile2105Leu	missense_variant	45/48
POLE	XM_011534797.4 linkuse as main transcript	c.5392A>C	p.Ile1798Leu	missense_variant	37/40
POLE	XM_011534802.4 linkuse as main transcript	c.3301A>C	p.Ile1101Leu	missense_variant	21/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLE	ENST00000320574.10 linkuse as main transcript	c.6313A>C	p.Ile2105Leu	missense_variant	45/49	1	NM_006231.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152194

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

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

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461754

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727170

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000657

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.091

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

T;.

Eigen

Benign

-0.080

Eigen_PC

Benign

0.0053

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.91

D;D

M_CAP

Benign

0.015

MetaRNN

Benign

0.32

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

M;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.8

N;N

REVEL

Benign

0.16

Sift

Uncertain

0.017

D;D

Sift4G

Uncertain

0.044

D;D

Polyphen

0.011

B;.

Vest4

0.48

MutPred

0.52

Gain of catalytic residue at L2102 (P = 0.0648);.;

MVP

0.32

MPC

0.20

ClinPred

0.82

GERP RS

4.0

Varity_R

0.24

gMVP

0.58

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

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over