rs692003

chr2-218809759-G-Achr2-218809759-G-Cchr2-218809759-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000784.4(CYP27A1):c.438G>A(p.Pro146=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,612,716 control chromosomes in the GnomAD database, including 2,007 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.064 (1032 hom., cov: 31)
  • Exomes 𝑓: 0.0068 (975 hom.)
• Consequence: CYP27A1 NM_000784.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.632

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 2-218809759-G-A is Benign according to our data. Variant chr2-218809759-G-A is described in ClinVar as [Benign]. Clinvar id is 65870.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-218809759-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.632 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.217 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP27A1	NM_000784.4	c.438G>A	p.Pro146=	synonymous_variant	2/9	ENST00000258415.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP27A1	ENST00000258415.9	c.438G>A	p.Pro146=	synonymous_variant	2/9	1	NM_000784.4	P1

Frequencies

GnomAD3 genomes AF: 0.0637 AC: 9685 AN: 152082 Hom.: 1022 Cov.: 31

Gnomad AFR AF: 0.220

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0290

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000779

Gnomad OTH AF: 0.0426

GnomAD3 exomes AF: 0.0171 AC: 4274 AN: 250230 Hom.: 405 AF XY: 0.0122 AC XY: 1651 AN XY: 135252

Gnomad AFR exome AF: 0.225

Gnomad AMR exome AF: 0.0120

Gnomad ASJ exome AF: 0.000200

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00160

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000797

Gnomad OTH exome AF: 0.00950

GnomAD4 exome AF: 0.00676 AC: 9879 AN: 1460516 Hom.: 975 Cov.: 32 AF XY: 0.00580 AC XY: 4212 AN XY: 726338

Gnomad4 AFR exome AF: 0.231

Gnomad4 AMR exome AF: 0.0135

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00142

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000378

Gnomad4 OTH exome AF: 0.0153

GnomAD4 genome AF: 0.0640 AC: 9742 AN: 152200 Hom.: 1032 Cov.: 31 AF XY: 0.0624 AC XY: 4645 AN XY: 74440

Gnomad4 AFR AF: 0.221

Gnomad4 AMR AF: 0.0290

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000779

Gnomad4 OTH AF: 0.0421

Alfa AF: 0.0109 Hom.: 203

Bravo AF: 0.0726

Asia WGS AF: 0.0190 AC: 67 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.00136

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 29, 2017	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Cholestanol storage disease Benign:4

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	curation	GeneReviews	Aug 01, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 24, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 05, 2019

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
Cadd	Benign	6.7
Dann	Benign	0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs692003; hg19: chr2-219674482;