rs386810227
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM2BP6_Very_Strong
The NM_002691.4(POLD1):c.3218+9_3218+10delCAinsTG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_002691.4 intron
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 |
---|---|---|---|---|---|---|---|---|
POLD1 | NM_002691.4 | c.3218+9_3218+10delCAinsTG | intron_variant | Intron 26 of 26 | ENST00000440232.7 | NP_002682.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
POLD1 | ENST00000440232.7 | c.3218+9_3218+10delCAinsTG | intron_variant | Intron 26 of 26 | 1 | NM_002691.4 | ENSP00000406046.1 | |||
ENSG00000142539 | ENST00000599632.1 | c.425+9_425+10delCAinsTG | intron_variant | Intron 5 of 9 | 5 | ENSP00000473233.1 |
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD4 genome Cov.: 34
ClinVar
Submissions by phenotype
not provided Benign:2
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Colorectal cancer, susceptibility to, 10 Benign:2
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not specified Benign:1
Variant summary: POLD1 c.3218+9_3218+10delinsTG alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was inferred to be at a frequency of 0.0052 in 226738 control chromosomes in the gnomAD database, including 10 homozygotes. The observed variant frequency is approximately 368-fold of the estimated maximal expected allele frequency for a pathogenic variant in POLD1 causing Colorectal Cancer phenotype (1.4e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.3218+9_3218+10delinsTG in individuals affected with Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. All laboratories classified the variant as benign/likely benign. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. -
Carcinoma of colon Benign:1
The POLD1 c.3218+9_3218+10delinsTG variant was not identified in the literature nor was it identified in the ClinVar database. The variant was only identified in dbSNP (ID: rs386810227) as "With other allele". The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). However, the POLD1 c.3218+9C>T variant was identified in control databases in 1197 of 231534 chromosomes (10 homozygous) at a frequency of 0.005 and the POLD1 c.3218+10A>G variant was identified in control databases in 10250 of 231916 chromosomes (1374 homozygous) at a frequency of 0.04 (Genome Aggregation Database Feb 27, 2017). 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 the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at