rs11677711

Variant names:

• chr2-218804652-T-G
• rs11677711
• NM_000784.4:c.256-4925T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000784.4(CYP27A1):​c.256-4925T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0306 in 152,366 control chromosomes in the GnomAD database, including 123 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.031 (123 hom., cov: 33)
• Consequence: CYP27A1 NM_000784.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.812
• Publications: 7 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0306 (4665/152366) while in subpopulation NFE AF = 0.0454 (3088/68038). AF 95% confidence interval is 0.0441. There are 123 homozygotes in GnomAd4. There are 2238 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 123 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.256-4925T>G		intron	N/A	NP_000775.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP27A1	ENST00000258415.9	TSL:1 MANE Select	c.256-4925T>G		intron	N/A	ENSP00000258415.4
	CYP27A1	ENST00000901552.1		c.256-4925T>G		intron	N/A	ENSP00000571611.1
	CYP27A1	ENST00000901553.1		c.256-4925T>G		intron	N/A	ENSP00000571612.1

Frequencies

GnomAD3 genomes AF: 0.0306 AC: 4664 AN: 152248 Hom.: 123 Cov.: 33

Gnomad AFR AF: 0.00755

Gnomad AMI AF: 0.171

Gnomad AMR AF: 0.0245

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.0562

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0454

Gnomad OTH AF: 0.0234

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0306 AC: 4665 AN: 152366 Hom.: 123 Cov.: 33 AF XY: 0.0300 AC XY: 2238 AN XY: 74514

African (AFR) AF: 0.00753 AC: 313 AN: 41594

American (AMR) AF: 0.0244 AC: 374 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 66 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00435 AC: 21 AN: 4830

European-Finnish (FIN) AF: 0.0562 AC: 597 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0454 AC: 3088 AN: 68038

Other (OTH) AF: 0.0232 AC: 49 AN: 2114

Alfa AF: 0.0368 Hom.: 217

Bravo AF: 0.0285

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	8.2
DANN	Benign	0.71
PhyloP100		0.81
Mutation Taster		=100/0	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: rs11677711; hg19: chr2-219669375;