chr12-132632794-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS1

The NM_006231.4(POLE):​c.6006G>A​(p.Ala2002Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,603,298 control chromosomes in the GnomAD database, including 1 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00010 ( 1 hom. )

Consequence

POLE
NM_006231.4 splice_region, synonymous

Scores

2
Splicing: ADA: 0.00004198
2

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -4.00
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 Benign. Variant got -17 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.83).
BP6
Variant 12-132632794-C-T is Benign according to our data. Variant chr12-132632794-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 384468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132632794-C-T is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=-4 with no splicing effect.
BS1
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000105 (152/1451100) while in subpopulation MID AF= 0.00191 (11/5752). AF 95% confidence interval is 0.00107. There are 1 homozygotes in gnomad4_exome. There are 90 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
POLENM_006231.4 linkc.6006G>A p.Ala2002Ala splice_region_variant, synonymous_variant 44/49 ENST00000320574.10 NP_006222.2 Q07864
POLEXM_011534795.4 linkc.6006G>A p.Ala2002Ala splice_region_variant, synonymous_variant 44/48 XP_011533097.1
POLEXM_011534797.4 linkc.5085G>A p.Ala1695Ala splice_region_variant, synonymous_variant 36/40 XP_011533099.1
POLEXM_011534802.4 linkc.2994G>A p.Ala998Ala splice_region_variant, synonymous_variant 20/24 XP_011533104.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
POLEENST00000320574.10 linkc.6006G>A p.Ala2002Ala splice_region_variant, synonymous_variant 44/491 NM_006231.4 ENSP00000322570.5 Q07864

Frequencies

GnomAD3 genomes
AF:
0.000184
AC:
28
AN:
152198
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000314
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000458
Gnomad ASJ
AF:
0.00144
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000209
AC:
50
AN:
239638
Hom.:
0
AF XY:
0.000214
AC XY:
28
AN XY:
130730
show subpopulations
Gnomad AFR exome
AF:
0.000322
Gnomad AMR exome
AF:
0.000235
Gnomad ASJ exome
AF:
0.000723
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000499
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000910
Gnomad OTH exome
AF:
0.000842
GnomAD4 exome
AF:
0.000105
AC:
152
AN:
1451100
Hom.:
1
Cov.:
32
AF XY:
0.000125
AC XY:
90
AN XY:
721704
show subpopulations
Gnomad4 AFR exome
AF:
0.000419
Gnomad4 AMR exome
AF:
0.000406
Gnomad4 ASJ exome
AF:
0.000851
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000524
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000207
Gnomad4 OTH exome
AF:
0.000316
GnomAD4 genome
AF:
0.000184
AC:
28
AN:
152198
Hom.:
0
Cov.:
32
AF XY:
0.000215
AC XY:
16
AN XY:
74356
show subpopulations
Gnomad4 AFR
AF:
0.000314
Gnomad4 AMR
AF:
0.000458
Gnomad4 ASJ
AF:
0.00144
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000150
Hom.:
0
Bravo
AF:
0.000253
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000273
EpiControl
AF:
0.0000593

ClinVar

Significance: Likely benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:4
Likely benign, criteria provided, single submitterclinical testingGeneDxMar 22, 2021- -
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 02, 2025- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenNov 01, 2023POLE: BP4, BP7 -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalMar 04, 2025- -
Colorectal cancer, susceptibility to, 12 Benign:1
Likely benign, criteria provided, single submitterclinical testingKCCC/NGS Laboratory, Kuwait Cancer Control CenterJul 07, 2023- -
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsJul 01, 2015This 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.83
CADD
Benign
0.0030
DANN
Benign
0.84

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000042
dbscSNV1_RF
Benign
0.0
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.

Other links and lift over

dbSNP: rs146902214; hg19: chr12-133209380; API