NM_183374.3:c.845_851dupCCATGCA

Variant names:

• chr10-93064519-T-TCCATGCA
• rs565866662
• NM_183374.3:c.845_851dupCCATGCA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:2 B:2
• Conservation: PhyloP100: 2.91
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• focal facial dermal dysplasia type IV

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ENSG00000285846 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_183374.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP26C1	NM_183374.3	MANE Select	c.845_851dupCCATGCA	p.Gln284HisfsTer129	frameshift	Exon 4 of 6	NP_899230.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP26C1	ENST00000651965.1	MANE Select	c.845_851dupCCATGCA	p.Gln284HisfsTer129	frameshift	Exon 4 of 6	ENSP00000498424.1
	ENSG00000285846	ENST00000648258.1		n.875_881dupCCATGCA		non_coding_transcript_exon	Exon 1 of 4
	CYP26C1	ENST00000624358.3	TSL:2	n.*1117-63_*1117-57dupCCATGCA		intron	N/A	ENSP00000485098.1

Frequencies

GnomAD3 genomes AF: 0.00204 AC: 311 AN: 152214 Hom.: 1 Cov.: 33

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

GnomAD2 exomes AF: 0.00211 AC: 529 AN: 250796 AF XY: 0.00218

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 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.: 7 Cov.: 30 AF XY: 0.00237 AC XY: 1719 AN XY: 726788

African (AFR) AF: 0.000269 AC: 9 AN: 33450

American (AMR) AF: 0.000179 AC: 8 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 86210

European-Finnish (FIN) AF: 0.00647 AC: 345 AN: 53352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00290 AC: 3222 AN: 1111542

Other (OTH) AF: 0.00167 AC: 101 AN: 60358

GnomAD4 genome AF: 0.00204 AC: 311 AN: 152332 Hom.: 1 Cov.: 33 AF XY: 0.00236 AC XY: 176 AN XY: 74484

African (AFR) AF: 0.000529 AC: 22 AN: 41588

American (AMR) AF: 0.000262 AC: 4 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00885 AC: 94 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00281 AC: 191 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00132 Hom.: 0

Bravo AF: 0.00141

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
3	1	-	Focal facial dermal dysplasia type IV (4)
2	-	1	not provided (3)
1	-	-	CYP26C1-related disorder (1)
-	1	-	not specified (1)
-	-	1	Optic nerve hypoplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.9
Mutation Taster		=29/171	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs565866662; hg19: chr10-94824276; COSMIC: COSV53651801; COSMIC: COSV53651801;