rs777503236

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_006231.4(POLE):​c.6547C>T​(p.Pro2183Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,611,624 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

POLE
NM_006231.4 missense

Scores

1
4
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.05
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.41295153).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
POLENM_006231.4 linkc.6547C>T p.Pro2183Ser missense_variant Exon 47 of 49 ENST00000320574.10 NP_006222.2 Q07864
POLEXM_011534795.4 linkc.6547C>T p.Pro2183Ser missense_variant Exon 47 of 48 XP_011533097.1
POLEXM_011534797.4 linkc.5626C>T p.Pro1876Ser missense_variant Exon 39 of 40 XP_011533099.1
POLEXM_011534802.4 linkc.3535C>T p.Pro1179Ser missense_variant Exon 23 of 24 XP_011533104.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
POLEENST00000320574.10 linkc.6547C>T p.Pro2183Ser missense_variant Exon 47 of 49 1 NM_006231.4 ENSP00000322570.5 Q07864

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152234
Hom.:
0
Cov.:
33
show subpopulations
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:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000121
AC:
3
AN:
248952
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
134752
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.0000994
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.00000617
AC:
9
AN:
1459390
Hom.:
0
Cov.:
34
AF XY:
0.00000551
AC XY:
4
AN XY:
726104
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000540
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152234
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74364
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:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Mar 11, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 540701). This variant has not been reported in the literature in individuals affected with POLE-related conditions. This variant is present in population databases (rs777503236, gnomAD 0.01%). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2183 of the POLE protein (p.Pro2183Ser). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.013
T
BayesDel_noAF
Benign
-0.16
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.44
T;.
Eigen
Benign
0.18
Eigen_PC
Uncertain
0.33
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Benign
0.75
T;T
M_CAP
Benign
0.0076
T
MetaRNN
Benign
0.41
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.3
L;.
PrimateAI
Uncertain
0.67
T
PROVEAN
Benign
-2.2
N;N
REVEL
Benign
0.16
Sift
Benign
0.13
T;T
Sift4G
Benign
0.11
T;T
Polyphen
0.035
B;.
Vest4
0.60
MutPred
0.48
Gain of catalytic residue at A2180 (P = 0.0013);.;
MVP
0.37
MPC
0.23
ClinPred
0.30
T
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.21
gMVP
0.33

Splicing

Name
Calibrated prediction
Score
Prediction
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.

Other links and lift over

dbSNP: rs777503236; hg19: chr12-133202341; API