Variant rs565866662 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 8P and 4B. PVS1BS2

The NM_183374.3(CYP26C1):c.845_851dupCCATGCA(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

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:2B:2

Conservation

PhyloP100: 2.91

Variant links:

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]

CYP26C1 links:

ENSG00000285846 (HGNC:):

ENSG00000285846 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP26C1	NM_183374.3 link	c.845_851dupCCATGCA	p.Gln284HisfsTer129	frameshift_variant	Exon 4 of 6	ENST00000651965.1	NP_899230.2	Q6V0L0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CYP26C1	ENST00000651965.1 link	c.845_851dupCCATGCA	p.Gln284HisfsTer129	frameshift_variant	Exon 4 of 6		NM_183374.3	ENSP00000498424.1	Q6V0L0
ENSG00000285846	ENST00000648258.1 link	n.875_881dupCCATGCA		non_coding_transcript_exon_variant	Exon 1 of 4
CYP26C1	ENST00000624358.3 link	n.1117-63_1117-57dupCCATGCA		intron_variant	Intron 3 of 5	2		ENSP00000485098.1	A0A096LNL5

Frequencies

GnomAD3 genomes

AF:

0.00204

AC:

311

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00885

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00281

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00211

AC:

529

AN:

250796

Hom.:

AF XY:

0.00218

AC XY:

295

AN XY:

135520

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00716

Gnomad NFE exome

AF:

0.00305

Gnomad OTH exome

AF:

0.00213

GnomAD4 exome

AF:

0.00252

AC:

3688

AN:

1461124

Hom.:

Cov.:

AF XY:

0.00237

AC XY:

1719

AN XY:

726788

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00647

Gnomad4 NFE exome

AF:

0.00290

Gnomad4 OTH exome

AF:

0.00167

GnomAD4 genome

AF:

0.00204

AC:

311

AN:

152332

Hom.:

Cov.:

AF XY:

0.00236

AC XY:

176

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.000529

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00885

Gnomad4 NFE

AF:

0.00281

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00132

Hom.:

Bravo

AF:

0.00141

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Focal facial dermal dysplasia type IV

Pathogenic:2Uncertain:1

Feb 15, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2024

Daryl Scott Lab, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PS3, PS4, BS1 -

not provided

Pathogenic:2Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 13, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect with this variant demonstrating 4% of enzyme activity as compared to wild-type (PMID: 23161670); Frameshift variant predicted to result in abnormal protein length as the last 239 amino acid(s) are replaced with 128 different amino acid(s); This variant is associated with the following publications: (PMID: 32040484, 34426522, 23161670, 29263414) -

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CYP26C1: PVS1, PM2, PM3, PP4 -

CYP26C1-related disorder

Pathogenic:1

Mar 25, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CYP26C1 c.845_851dup7 variant is predicted to result in a frameshift and premature protein termination (p.Gln284Hisfs*129). This variant was reported in the compound heterozygous or homozygous state in multiple individuals with focal facial dermal dysplasia IV (Slavotinek et al. 2013. PubMed ID: 23161670, described as c.844_851dupCCATGCA; Lee et al. 2018. PubMed ID: 29263414). This variant is reported in 0.70% of alleles in individuals of European (Finnish) descent in gnomAD. This variant has also been observed in the heterozygous state in an individual with optic nerve hypoplasia (Table 2, Dahl et al. 2020. PubMed ID: 32040484). Frameshift variants in CYP26C1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

not specified

Uncertain:1

Nov 20, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Rare Disease Group, Clinical Genetics, Karolinska Institutet

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over