rs368662693
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBP6BP7
The NM_006231.4(POLE):c.6135C>T(p.Pro2045Pro) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000564 in 1,613,844 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_006231.4 splice_region, synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POLE | NM_006231.4 | c.6135C>T | p.Pro2045Pro | splice_region_variant, synonymous_variant | Exon 44 of 49 | ENST00000320574.10 | NP_006222.2 | |
POLE | XM_011534795.4 | c.6135C>T | p.Pro2045Pro | splice_region_variant, synonymous_variant | Exon 44 of 48 | XP_011533097.1 | ||
POLE | XM_011534797.4 | c.5214C>T | p.Pro1738Pro | splice_region_variant, synonymous_variant | Exon 36 of 40 | XP_011533099.1 | ||
POLE | XM_011534802.4 | c.3123C>T | p.Pro1041Pro | splice_region_variant, synonymous_variant | Exon 20 of 24 | XP_011533104.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152150Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000838 AC: 21AN: 250618Hom.: 0 AF XY: 0.0000811 AC XY: 11AN XY: 135648
GnomAD4 exome AF: 0.0000588 AC: 86AN: 1461694Hom.: 0 Cov.: 32 AF XY: 0.0000536 AC XY: 39AN XY: 727134
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152150Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74334
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:1
Variant classified as Uncertain Significance - Favor Benign. The p.Pro2045Pro va riant in POLE has not been previously reported in individuals with colorectal ca ncer but has been identified in 5/8596 of East Asian chromosomes by the Exome Ag gregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs368662693). This variant is located in the last three bases of the exon, which is part of th e 5? splice region. Computational tools do not suggest an impact to splicing. Ho wever, this information is not predictive enough to rule out pathogenicity. In s ummary, the clinical significance of the p.Pro2045Pro variant is uncertain altho ugh it is suspected to be more likely benign. -
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Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
This 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. -
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not provided Benign:2
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POLE-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at