rs187723732

Variant names:

• chr2-218781978-C-A
• rs187723732
• ENST00000901552.1:c.-205C>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000901552.1(CYP27A1):​c.-205C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 629,320 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0033 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00041 (0 hom.)
• Consequence: CYP27A1 ENST00000901552.1 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.0290
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 2-218781978-C-A is Benign according to our data. Variant chr2-218781978-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 334364.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00334 (509/152340) while in subpopulation AFR AF = 0.0114 (472/41584). AF 95% confidence interval is 0.0105. There are 2 homozygotes in GnomAd4. There are 246 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000901552.1. 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.-205C>A		upstream_gene	N/A	NP_000775.1	Q02318

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP27A1	ENST00000901552.1		c.-205C>A		5_prime_UTR	Exon 1 of 9	ENSP00000571611.1
	CYP27A1	ENST00000901553.1		c.-205C>A		5_prime_UTR	Exon 1 of 9	ENSP00000571612.1
	CYP27A1	ENST00000901554.1		c.-205C>A		5_prime_UTR	Exon 1 of 9	ENSP00000571613.1

Frequencies

GnomAD3 genomes AF: 0.00332 AC: 505 AN: 152222 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000955

GnomAD4 exome AF: 0.000409 AC: 195 AN: 476980 Hom.: 0 Cov.: 6 AF XY: 0.000324 AC XY: 80 AN XY: 246792

African (AFR) AF: 0.0137 AC: 130 AN: 9492

American (AMR) AF: 0.000785 AC: 10 AN: 12744

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12422

East Asian (EAS) AF: 0.00 AC: 0 AN: 26038

South Asian (SAS) AF: 0.00 AC: 0 AN: 39506

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29156

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1956

European-Non Finnish (NFE) AF: 0.0000470 AC: 15 AN: 319424

Other (OTH) AF: 0.00152 AC: 40 AN: 26242

GnomAD4 genome AF: 0.00334 AC: 509 AN: 152340 Hom.: 2 Cov.: 32 AF XY: 0.00330 AC XY: 246 AN XY: 74490

African (AFR) AF: 0.0114 AC: 472 AN: 41584

American (AMR) AF: 0.00170 AC: 26 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68024

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00298 Hom.: 0

Bravo AF: 0.00392

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Cholestanol storage disease (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	6.5
DANN	Benign	0.69
PhyloP100		0.029
PromoterAI		0.046	Neutral
Mutation Taster		=300/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs187723732; hg19: chr2-219646701;