rs886041342

Variant names:

• chr2-218782184-TGGCTGCGCTG-T
• rs886041342
• NM_000784.4:c.11_20delTGGGCTGCGC

Your query was ambiguous. Multiple possible variants found:

• chr2-218782184-TGGCTGCGCTG-T
• chr2-218782184-TGGCTGCGCTG-TGGCTGCGCTGGGCTGCGCTG

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_000784.4(CYP27A1):​c.11_20delTGGGCTGCGC​(p.Leu4ArgfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000289 in 1,384,210 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: CYP27A1 NM_000784.4 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.60
• Publications: 0 publications found

Genes affected

CYP27A1 (HGNC:2605): (cytochrome P450 family 27 subfamily A 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 mitochondrial protein oxidizes cholesterol intermediates as part of the bile synthesis pathway. Since the conversion of cholesterol to bile acids is the major route for removing cholesterol from the body, this protein is important for overall cholesterol homeostasis. Mutations in this gene cause cerebrotendinous xanthomatosis, a rare autosomal recessive lipid storage disease. [provided by RefSeq, Jul 2008]

CYP27A1 Gene-Disease associations (from GenCC):

• cerebrotendinous xanthomatosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet, ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 175 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000784.4. 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
	CYP27A1	NM_000784.4	MANE Select	c.11_20delTGGGCTGCGC	p.Leu4ArgfsTer3	frameshift	Exon 1 of 9	NP_000775.1	Q02318

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP27A1	ENST00000258415.9	TSL:1 MANE Select	c.11_20delTGGGCTGCGC	p.Leu4ArgfsTer3	frameshift	Exon 1 of 9	ENSP00000258415.4	Q02318
	CYP27A1	ENST00000901552.1		c.11_20delTGGGCTGCGC	p.Leu4ArgfsTer3	frameshift	Exon 1 of 9	ENSP00000571611.1
	CYP27A1	ENST00000901553.1		c.11_20delTGGGCTGCGC	p.Leu4ArgfsTer3	frameshift	Exon 1 of 9	ENSP00000571612.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000289 AC: 4 AN: 1384210 Hom.: 0 AF XY: 0.00000586 AC XY: 4 AN XY: 683160

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31354

American (AMR) AF: 0.00 AC: 0 AN: 35626

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25108

East Asian (EAS) AF: 0.00 AC: 0 AN: 35674

South Asian (SAS) AF: 0.0000506 AC: 4 AN: 79114

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37512

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4100

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078062

Other (OTH) AF: 0.00 AC: 0 AN: 57660

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000286219), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6
Mutation Taster		=25/175	disease causing

Splicing

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

Other links and lift over

dbSNP: rs886041342; hg19: chr2-219646907;