rs114768494

Variant names:

• chr2-218812578-C-T
• rs114768494
• NM_000784.4:c.673C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000784.4(CYP27A1):​c.673C>T​(p.Arg225Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000745 in 1,614,192 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R225P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0037 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00044 (5 hom.)
• Consequence: CYP27A1 NM_000784.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.26
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012562275).
• BP6: Variant 2-218812578-C-T is Benign according to our data. Variant chr2-218812578-C-T is described in ClinVar as Benign. ClinVar VariationId is 256798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00372 (567/152314) while in subpopulation AFR AF = 0.0129 (536/41558). AF 95% confidence interval is 0.012. There are 6 homozygotes in GnomAd4. There are 289 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

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.673C>T	p.Arg225Cys	missense	Exon 4 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.673C>T	p.Arg225Cys	missense	Exon 4 of 9	ENSP00000258415.4	Q02318
	CYP27A1	ENST00000901552.1		c.673C>T	p.Arg225Cys	missense	Exon 4 of 9	ENSP00000571611.1
	CYP27A1	ENST00000901553.1		c.691C>T	p.Arg231Cys	missense	Exon 4 of 9	ENSP00000571612.1

Frequencies

GnomAD3 genomes AF: 0.00373 AC: 568 AN: 152196 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

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: 0.00

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00106 AC: 266 AN: 251398 AF XY: 0.000765

Gnomad AFR exome AF: 0.0150

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000435 AC: 636 AN: 1461878 Hom.: 5 Cov.: 32 AF XY: 0.000373 AC XY: 271 AN XY: 727238

African (AFR) AF: 0.0164 AC: 548 AN: 33468

American (AMR) AF: 0.000402 AC: 18 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1112008

Other (OTH) AF: 0.000861 AC: 52 AN: 60396

GnomAD4 genome AF: 0.00372 AC: 567 AN: 152314 Hom.: 6 Cov.: 32 AF XY: 0.00388 AC XY: 289 AN XY: 74478

African (AFR) AF: 0.0129 AC: 536 AN: 41558

American (AMR) AF: 0.00150 AC: 23 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00111 Hom.: 2

Bravo AF: 0.00399

ESP6500AA AF: 0.0109 AC: 48

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00120 AC: 146

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Cholestanol storage disease (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	0.060	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		1.3
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-7.8	D
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.93
MVP		0.88
MPC		0.84
ClinPred		0.12	T
GERP RS		2.7
Varity_R		0.84
gMVP		0.87
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs114768494; hg19: chr2-219677301; COSMIC: COSV51469825;