rs1555220905

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

The ENST00000320574.10(POLE):​c.6192C>T​(p.Phe2064=) variant causes a synonymous change. The variant allele was found at a frequency of 0.00000205 in 1,461,694 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

POLE
ENST00000320574.10 synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 5.79
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.28).
BP6
Variant 12-132632453-G-A is Benign according to our data. Variant chr12-132632453-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 540833.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
POLENM_006231.4 linkuse as main transcriptc.6192C>T p.Phe2064= synonymous_variant 45/49 ENST00000320574.10 NP_006222.2
POLEXM_011534795.4 linkuse as main transcriptc.6192C>T p.Phe2064= synonymous_variant 45/48 XP_011533097.1
POLEXM_011534797.4 linkuse as main transcriptc.5271C>T p.Phe1757= synonymous_variant 37/40 XP_011533099.1
POLEXM_011534802.4 linkuse as main transcriptc.3180C>T p.Phe1060= synonymous_variant 21/24 XP_011533104.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
POLEENST00000320574.10 linkuse as main transcriptc.6192C>T p.Phe2064= synonymous_variant 45/491 NM_006231.4 ENSP00000322570 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461694
Hom.:
0
Cov.:
32
AF XY:
0.00000413
AC XY:
3
AN XY:
727168
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.000115
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJan 20, 2020Not observed in large population cohorts (Lek 2016) In silico analysis, which includes splice predictors and evolutionary conservation, supports that this variant does not alter protein structure/function Has not been previously published as pathogenic or benign to our knowledge -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 09, 2024- -
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsMar 29, 2018This 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
-0.28
CADD
Benign
14
DANN
Benign
0.92

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.20
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.20
Position offset: -13

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: rs1555220905; hg19: chr12-133209039; API