2-218781813-T-C

Variant names:

• chr2-218781813-T-C
• rs182545847
• ENST00000901552.1:c.-370T>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The ENST00000901552.1(CYP27A1):​c.-370T>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000366 in 92,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0083 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000089 (0 hom.)
• Consequence: CYP27A1 ENST00000901552.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.910
• Publications: 1 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00826 (26/3148) while in subpopulation AMR AF = 0.0324 (9/278). AF 95% confidence interval is 0.0169. There are 0 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP27A1	ENST00000901552.1		c.-370T>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	ENSP00000571611.1
	CYP27A1	ENST00000901553.1		c.-370T>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	ENSP00000571612.1
	CYP27A1	ENST00000901554.1		c.-370T>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	ENSP00000571613.1

Frequencies

GnomAD3 genomes AF: 0.00826 AC: 26 AN: 3146 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00306

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0326

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00795

Gnomad OTH AF: 0.0313

GnomAD4 exome AF: 0.0000892 AC: 8 AN: 89652 Hom.: 0 Cov.: 0 AF XY: 0.000154 AC XY: 7 AN XY: 45464

African (AFR) AF: 0.00 AC: 0 AN: 2298

American (AMR) AF: 0.00 AC: 0 AN: 2410

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2942

East Asian (EAS) AF: 0.00 AC: 0 AN: 4980

South Asian (SAS) AF: 0.00 AC: 0 AN: 6856

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5906

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 456

European-Non Finnish (NFE) AF: 0.0000862 AC: 5 AN: 58024

Other (OTH) AF: 0.000519 AC: 3 AN: 5780

GnomAD4 genome AF: 0.00826 AC: 26 AN: 3148 Hom.: 0 Cov.: 31 AF XY: 0.00786 AC XY: 12 AN XY: 1526

African (AFR) AF: 0.00306 AC: 2 AN: 654

American (AMR) AF: 0.0324 AC: 9 AN: 278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 106

East Asian (EAS) AF: 0.00 AC: 0 AN: 96

South Asian (SAS) AF: 0.00 AC: 0 AN: 44

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 158

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4

European-Non Finnish (NFE) AF: 0.00795 AC: 14 AN: 1760

Other (OTH) AF: 0.0313 AC: 1 AN: 32

Alfa AF: 0.0000693 Hom.: 0

Bravo AF: 0.000223

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Cholestanol storage disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.9
DANN	Benign	0.26
PhyloP100		-0.91
PromoterAI		0.038	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs182545847; hg19: chr2-219646536;