NM_006231.4:c.2469-15G>A
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
The NM_006231.4(POLE):c.2469-15G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,608,352 control chromosomes in the GnomAD database, including 2,061 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Consequence
NM_006231.4 intron
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0649 AC: 9874AN: 152138Hom.: 1034 Cov.: 32
GnomAD3 exomes AF: 0.0175 AC: 4391AN: 250480Hom.: 478 AF XY: 0.0127 AC XY: 1726AN XY: 135442
GnomAD4 exome AF: 0.00697 AC: 10150AN: 1456096Hom.: 1020 Cov.: 30 AF XY: 0.00604 AC XY: 4376AN XY: 724758
GnomAD4 genome AF: 0.0651 AC: 9914AN: 152256Hom.: 1041 Cov.: 32 AF XY: 0.0623 AC XY: 4637AN XY: 74442
ClinVar
Submissions by phenotype
not specified Benign:3
- -
- -
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:3
- -
Variant summary: c.2469-15G>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 have a major effect normal on 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 0.022 (2623/120098 chrs tested), predominantly in individuals of African descent 0.237 (2429/10264 chrs tested), including numerous homozygous occurrences. The observed frequency greatly exceeds the maximum expected allele frequency for a pathogenic variant of 0.00001%, suggesting that it is a benign polymorphism. Taking together, based on the prevalence of this variant in general population the variant was classified as Benign. -
- -
Colorectal cancer, susceptibility to, 12 Benign:1
- -
Polymerase proofreading-related adenomatous polyposis Benign:1
The POLE c.2469-15G>A variant was not identified in the literature. The variant was identified in dbSNP (ID: rs5744833) as "With Benign allele” and ClinVar (classified as benign by GeneDx and Integrated Genetics/Laboratory Corporation of America). The variant was identified in control databases in 6160 of 276308 chromosomes (636 homozygous) at a frequency of 0.02, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 5539 of 23994 chromosomes (freq: 0.23), Other in 64 of 6450 chromosomes (freq: 0.01), Latino in 406 of 34410 chromosomes (freq: 0.01), European in 134 of 126316 chromosomes (freq: 0.001), Ashkenazi Jewish in 9 of 10138 chromosomes (freq: 0.0008), and South Asian in 8 of 30770 chromosomes (freq: 0.0003); it was not observed in the East Asian or Finnish populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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
This alteration is classified as 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at