2-218781978-C-A

Variant names:

• chr2-218781978-C-A
• rs187723732
• ENST00000494263.5:n.230C>A

Variant summary

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

The ENST00000494263.5(CYP27A1):​n.230C>A variant causes a non coding transcript exon 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 ENST00000494263.5 non_coding_transcript_exon
• 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: Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Genomics England PanelApp, G2P

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 id is 334364.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP27A1	NM_000784.4	c.-205C>A		upstream_gene_variant		ENST00000258415.9	NP_000775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP27A1	ENST00000494263.5	n.230C>A		non_coding_transcript_exon_variant	Exon 1 of 7	2
CYP27A1	ENST00000258415.9	c.-205C>A		upstream_gene_variant		1	NM_000784.4	ENSP00000258415.4
CYP27A1	ENST00000445971.1	n.-205C>A		upstream_gene_variant		5		ENSP00000404945.1
CYP27A1	ENST00000466602.1	n.-196C>A		upstream_gene_variant		2

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cholestanol storage disease Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Oct 14, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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;