2-218782177-C-T

Position:

chr2-218782177-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000784.4(CYP27A1):c.-6C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 1,535,458 control chromosomes in the GnomAD database, including 17 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 0.0068 ( 11 hom., cov: 32)

Exomes 𝑓: 0.00069 ( 6 hom. )

Consequence

CYP27A1
NM_000784.4 5_prime_UTR

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: -0.278

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 2-218782177-C-T is Benign according to our data. Variant chr2-218782177-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 193124.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2}. Variant chr2-218782177-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0068 (1036/152348) while in subpopulation AFR AF= 0.0236 (981/41578). AF 95% confidence interval is 0.0224. There are 11 homozygotes in gnomad4. There are 494 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP27A1	NM_000784.4 linkuse as main transcript	c.-6C>T		5_prime_UTR_variant	1/9	ENST00000258415.9

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Appris
CYP27A1	ENST00000258415.9 linkuse as main transcript	c.-6C>T	5_prime_UTR_variant	1/9	1	NM_000784.4	P1
CYP27A1	ENST00000466602.1 linkuse as main transcript	n.4C>T	non_coding_transcript_exon_variant	1/3	2
CYP27A1	ENST00000494263.5 linkuse as main transcript	n.429C>T	non_coding_transcript_exon_variant	1/7	2
CYP27A1	ENST00000445971.1 linkuse as main transcript	c.-6C>T	5_prime_UTR_variant, NMD_transcript_variant	1/5	5

Frequencies

GnomAD3 genomes

AF:

0.00676

AC:

1029

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0235

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00255

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:

0.000147

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00130

AC:

172

AN:

132192

Hom.:

AF XY:

0.000873

AC XY:

AN XY:

72182

show subpopulations

Gnomad AFR exome

AF:

0.0229

Gnomad AMR exome

AF:

0.000943

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000133

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000608

Gnomad OTH exome

AF:

0.000750

GnomAD4 exome

AF:

0.000689

AC:

953

AN:

1383110

Hom.:

Cov.:

AF XY:

0.000539

AC XY:

368

AN XY:

682658

show subpopulations

Gnomad4 AFR exome

AF:

0.0241

Gnomad4 AMR exome

AF:

0.00104

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000759

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000399

Gnomad4 OTH exome

AF:

0.00189

GnomAD4 genome

AF:

0.00680

AC:

1036

AN:

152348

Hom.:

Cov.:

AF XY:

0.00663

AC XY:

494

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.0236

Gnomad4 AMR

AF:

0.00255

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000344

Hom.:

Bravo

AF:

0.00752

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cholestanol storage disease

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 18, 2019	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 05, 2015

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 07, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

DANN

Benign

0.72

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over