rs61733619

Variant names:

• chr2-218812967-A-G
• rs61733619
• NM_000784.4:c.888A>G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000784.4(CYP27A1):​c.888A>G​(p.Gln296Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0215 in 1,614,122 control chromosomes in the GnomAD database, including 460 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (35 hom., cov: 32)
  • Exomes 𝑓: 0.022 (425 hom.)
• Consequence: CYP27A1 NM_000784.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.21

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-218812967-A-G is Benign according to our data. Variant chr2-218812967-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 65618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-218812967-A-G is described in Lovd as [Benign]. Variant chr2-218812967-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.21 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0162 (2461/152274) while in subpopulation NFE AF= 0.0246 (1675/68012). AF 95% confidence interval is 0.0236. There are 35 homozygotes in gnomad4. There are 1120 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 35 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP27A1	NM_000784.4	c.888A>G	p.Gln296Gln	synonymous_variant	Exon 5 of 9	ENST00000258415.9	NP_000775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP27A1	ENST00000258415.9	c.888A>G	p.Gln296Gln	synonymous_variant	Exon 5 of 9	1	NM_000784.4	ENSP00000258415.4

Frequencies

GnomAD3 genomes AF: 0.0162 AC: 2463 AN: 152156 Hom.: 35 Cov.: 32

Gnomad AFR AF: 0.00439

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0164

Gnomad ASJ AF: 0.00577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00766

Gnomad FIN AF: 0.0199

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0246

Gnomad OTH AF: 0.0244

GnomAD3 exomes AF: 0.0176 AC: 4415 AN: 251410 Hom.: 56 AF XY: 0.0177 AC XY: 2405 AN XY: 135870

Gnomad AFR exome AF: 0.00449

Gnomad AMR exome AF: 0.0147

Gnomad ASJ exome AF: 0.00675

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00986

Gnomad FIN exome AF: 0.0246

Gnomad NFE exome AF: 0.0247

Gnomad OTH exome AF: 0.0199

GnomAD4 exome AF: 0.0220 AC: 32190 AN: 1461848 Hom.: 425 Cov.: 32 AF XY: 0.0221 AC XY: 16050 AN XY: 727222

Gnomad4 AFR exome AF: 0.00388

Gnomad4 AMR exome AF: 0.0159

Gnomad4 ASJ exome AF: 0.00658

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0101

Gnomad4 FIN exome AF: 0.0261

Gnomad4 NFE exome AF: 0.0248

Gnomad4 OTH exome AF: 0.0191

GnomAD4 genome AF: 0.0162 AC: 2461 AN: 152274 Hom.: 35 Cov.: 32 AF XY: 0.0150 AC XY: 1120 AN XY: 74462

Gnomad4 AFR AF: 0.00438

Gnomad4 AMR AF: 0.0164

Gnomad4 ASJ AF: 0.00577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00767

Gnomad4 FIN AF: 0.0199

Gnomad4 NFE AF: 0.0246

Gnomad4 OTH AF: 0.0242

Alfa AF: 0.0217 Hom.: 52

Bravo AF: 0.0160

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.0262

EpiControl AF: 0.0267

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cholestanol storage disease Benign:4

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 01, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

not provided Benign:3

May 25, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:1

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Dec 11, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.85
CADD	Benign	0.30
DANN	Benign	0.33
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61733619; hg19: chr2-219677690;