2-218782184-T-TGGCTGCGCTG
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000784.4(CYP27A1):c.11_20dupTGGGCTGCGC(p.Arg8GlyfsTer176) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000433 in 1,384,210 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000784.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CYP27A1 | ENST00000258415.9 | c.11_20dupTGGGCTGCGC | p.Arg8GlyfsTer176 | frameshift_variant | Exon 1 of 9 | 1 | NM_000784.4 | ENSP00000258415.4 | ||
CYP27A1 | ENST00000445971.1 | n.11_20dupTGGGCTGCGC | non_coding_transcript_exon_variant | Exon 1 of 5 | 5 | ENSP00000404945.1 | ||||
CYP27A1 | ENST00000466602.1 | n.20_29dupTGGGCTGCGC | non_coding_transcript_exon_variant | Exon 1 of 3 | 2 | |||||
CYP27A1 | ENST00000494263.5 | n.445_454dupTGGGCTGCGC | non_coding_transcript_exon_variant | Exon 1 of 7 | 2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000751 AC: 1AN: 133178Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 72660
GnomAD4 exome AF: 0.00000433 AC: 6AN: 1384210Hom.: 0 Cov.: 31 AF XY: 0.00000586 AC XY: 4AN XY: 683160
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Cholestanol storage disease Pathogenic:5
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This sequence change creates a premature translational stop signal (p.Arg8Glyfs*176) in the CYP27A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CYP27A1 are known to be pathogenic (PMID: 9392430, 10775536, 26937392). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with CYP27A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 280048). For these reasons, this variant has been classified as Pathogenic. -
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not provided Pathogenic:2
The c.11_20dup10 variant in the CYP27A1 gene has been reported previously in association with cerebrotendinous xanthomatosis in an affected sibling pair who was compound heterozygous for the c.11_20dup10 variant and a missense variant; alternate nomenclature c.11_20dupwas used (Tészás et al., 2006). The c.11_20dup10 variant causes a frameshift starting with codon Arginine 8, changes this amino acid to a Glycine residue, and creates a premature Stop codon at position 176 of the new reading frame, denoted p.Arg8GlyfsX176. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.11_20dup10 variant was not observed in approximately 4500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.11_20dup10 as a pathogenic variant. -
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at