chr12-132667656-C-T
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_006231.4(POLE):c.2174-8G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.014 in 1,613,788 control chromosomes in the GnomAD database, including 188 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
Consequence
NM_006231.4 splice_region, splice_polypyrimidine_tract, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLE | NM_006231.4 | c.2174-8G>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000320574.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLE | ENST00000320574.10 | c.2174-8G>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_006231.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0111 AC: 1686AN: 152190Hom.: 9 Cov.: 32
GnomAD3 exomes AF: 0.0119 AC: 2982AN: 251098Hom.: 27 AF XY: 0.0115 AC XY: 1562AN XY: 135708
GnomAD4 exome AF: 0.0143 AC: 20861AN: 1461480Hom.: 179 Cov.: 31 AF XY: 0.0138 AC XY: 10059AN XY: 727060
GnomAD4 genome ? AF: 0.0111 AC: 1687AN: 152308Hom.: 9 Cov.: 32 AF XY: 0.0108 AC XY: 805AN XY: 74466
ClinVar
Submissions by phenotype
not specified Benign:6
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 22, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 29, 2016 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 1.7% European, intronic - |
Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 18, 2016 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
not provided Benign:5
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 17, 2016 | Variant summary: c.2174-8G>A in POLE gene is an intronic change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at frequency of 0.012 (1461/121260 chrs tested), including 4 homozygous occurrences. The observed frequency exceeds the maximum expected allele frequency for a pathogenic variant of 0.000014, suggesting that it is a benign polymorphism. The variant of interest has been reported as Benign/Polymorphism by reputable database/clinical laboratory. Taking together, based on the prevalence of this variant in general population the variant was classified as Benign. - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Feb 16, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 07, 2023 | - - |
Colorectal cancer, susceptibility to, 12 Benign:1
Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Carcinoma of colon Benign:1
Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The POLE c.2174-8G>A variant was not identified in the literature nor was it identified in the Cosmic and MutDB databases. The variant was identified in dbSNP (ID: rs117409343) as “With other allele”, ClinVar and Clinvitae (5x as benign by Invitae, GeneDx, Quest diagnostics, Laboratory Corporation of America and likely benign by Laboratory for molecular Medicine). The variant was identified in control databases in 3277 of 276912 chromosomes (25 homozygous) at a frequency of 0.012 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 75 of 24034 chromosomes (freq: 0.003), Other in 88 of 6458 chromosomes (freq: 0.013), Latino in 291 of 34418 chromosomes (freq: 0.008), European Non-Finnish in 2146 of 126616 chromosomes (freq: 0.017), Ashkenazi Jewish in 87 of 10152 chromosomes (freq: 0.008), East Asian in 1 of 18870 chromosomes (freq: 0.000053), European Finnish in 502 of 25584 chromosomes (freq: 0.02), and South Asian in 87 of 30780 chromosomes (freq: 0.003). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, no assertion criteria provided | clinical testing | True Health Diagnostics | Feb 14, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at