rs565866662
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_183374.3(CYP26C1):c.845_851dup(p.Gln284HisfsTer129) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00248 in 1,613,456 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0020 ( 1 hom., cov: 33)
Exomes 𝑓: 0.0025 ( 7 hom. )
Consequence
CYP26C1
NM_183374.3 frameshift
NM_183374.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.91
Genes affected
CYP26C1 (HGNC:20577): (cytochrome P450 family 26 subfamily C member 1) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This enzyme is involved in the catabolism of all-trans- and 9-cis-retinoic acid, and thus contributes to the regulation of retinoic acid levels in cells and tissues. This gene is adjacent to a related gene on chromosome 10q23.33. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CYP26C1 | NM_183374.3 | c.845_851dup | p.Gln284HisfsTer129 | frameshift_variant | 4/6 | ENST00000651965.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CYP26C1 | ENST00000651965.1 | c.845_851dup | p.Gln284HisfsTer129 | frameshift_variant | 4/6 | NM_183374.3 | P1 | ||
CYP26C1 | ENST00000624358.3 | c.*1117-63_*1117-57dup | intron_variant, NMD_transcript_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00204 AC: 311AN: 152214Hom.: 1 Cov.: 33
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GnomAD3 exomes AF: 0.00211 AC: 529AN: 250796Hom.: 1 AF XY: 0.00218 AC XY: 295AN XY: 135520
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GnomAD4 exome AF: 0.00252 AC: 3688AN: 1461124Hom.: 7 Cov.: 30 AF XY: 0.00237 AC XY: 1719AN XY: 726788
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GnomAD4 genome ? AF: 0.00204 AC: 311AN: 152332Hom.: 1 Cov.: 33 AF XY: 0.00236 AC XY: 176AN XY: 74484
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:2Benign:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2024 | CYP26C1: PVS1, PM2, PM3, PP4 - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 20, 2023 | Published functional studies demonstrate a damaging effect with this variant demonstrating 4% of enzyme activity as compared to wild-type (Slavotinek et al., 2013); Frameshift variant predicted to result in protein truncation as the last 239 amino acids are replaced with 128 different amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 23161670, 32040484, 34426522, 29263414) - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 31, 2019 | - - |
Focal facial dermal dysplasia type IV Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 15, 2013 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 20, 2018 | Variant classified as Uncertain Significance - Favor Pathogenic. The p.Gln284His fsX129 variant in CYP26C1 has been reported in 3 homozygous and 2 compound heter ozygous individuals with focal facial dermal dysplasia 4 (FFDD 4)and segregated with disease in 1 affected relative (Slavotinek 2013, Lee 2018). This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 284 and leads to a premature termination codon 129 amino acids downstream. This termination codon occurs within the terminal 50 bases of the second to last exon and is, therefore, likely to escape nonsense mediated de cay (NMD) and result in a truncated protein. This variant has also been identifi ed in 0.7% (177/25112) of Finnish and 0.3% (392/128808) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org), which is higher than expected cons idering the rarity of FFDD 4. It has been speculated that this is due to incompl ete penetrance or under ascertainment (Slavotinek 2013); however, it is unclear at this time. In summary, while there is some suspicion for a pathogenic role, t he clinical significance of the p.Gln284HisfsX129 variant is uncertain due to co nflicting data. ACMG/AMP Criteria applied: PM3, PM4, BS1_Supporting. - |
Optic nerve hypoplasia Benign:1
Likely benign, criteria provided, single submitter | research | Rare Disease Group, Clinical Genetics, Karolinska Institutet | - | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at