rs141925556

Positions:

chrX-48528275-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM1BP4_ModerateBS1_SupportingBS2

The ENST00000495186.6(EBP):c.511C>T(p.Arg171Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000921 in 1,209,745 control chromosomes in the GnomAD database, including 2 homozygotes. There are 338 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R171H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00063 ( 0 hom., 19 hem., cov: 23)

Exomes 𝑓: 0.00095 ( 2 hom. 319 hem. )

Consequence

EBP
ENST00000495186.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1B:6

Conservation

PhyloP100: 2.73

Variant links:

Genes affected

EBP (HGNC:3133): (EBP cholestenol delta-isomerase) The protein encoded by this gene is an integral membrane protein of the endoplasmic reticulum. It is a high affinity binding protein for the antiischemic phenylalkylamine Ca2+ antagonist [3H]emopamil and the photoaffinity label [3H]azidopamil. It is similar to sigma receptors and may be a member of a superfamily of high affinity drug-binding proteins in the endoplasmic reticulum of different tissues. This protein shares structural features with bacterial and eukaryontic drug transporting proteins. It has four putative transmembrane segments and contains two conserved glutamate residues which may be involved in the transport of cationic amphiphilics. Another prominent feature of this protein is its high content of aromatic amino acid residues (>23%) in its transmembrane segments. These aromatic amino acid residues have been suggested to be involved in the drug transport by the P-glycoprotein. Mutations in this gene cause Chondrodysplasia punctata 2 (CDPX2; also known as Conradi-Hunermann syndrome). [provided by RefSeq, Jul 2008]

EBP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PM1

In a domain EXPERA (size 143) in uniprot entity EBP_HUMAN there are 42 pathogenic changes around while only 9 benign (82%) in ENST00000495186.6

BP4

Computational evidence support a benign effect (MetaRNN=0.13119799).

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00095 (1043/1097868) while in subpopulation NFE AF= 0.00113 (950/841958). AF 95% confidence interval is 0.00107. There are 2 homozygotes in gnomad4_exome. There are 319 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Hemizygotes in GnomAd4 at 19 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EBP	NM_006579.3 linkuse as main transcript	c.511C>T	p.Arg171Cys	missense_variant	5/5	ENST00000495186.6	NP_006570.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
EBP	ENST00000495186.6 linkuse as main transcript	c.511C>T	p.Arg171Cys	missense_variant	5/5	1	NM_006579.3	ENSP00000417052	P1
EBP	ENST00000276096.10 linkuse as main transcript	n.469C>T		non_coding_transcript_exon_variant	5/5	2
EBP	ENST00000498425.1 linkuse as main transcript	n.632C>T		non_coding_transcript_exon_variant	5/5	3
EBP	ENST00000446158.5 linkuse as main transcript			downstream_gene_variant		5		ENSP00000390031

Frequencies

GnomAD3 genomes

AF:

0.000635

AC:

AN:

111825

Hom.:

Cov.:

AF XY:

0.000559

AC XY:

AN XY:

34001

show subpopulations

Gnomad AFR

AF:

0.000162

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000667

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000331

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00105

Gnomad OTH

AF:

0.000670

GnomAD3 exomes

AF:

0.000641

AC:

116

AN:

180993

Hom.:

AF XY:

0.000624

AC XY:

AN XY:

65753

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000951

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000107

Gnomad FIN exome

AF:

0.000189

Gnomad NFE exome

AF:

0.00102

Gnomad OTH exome

AF:

0.000670

GnomAD4 exome

AF:

0.000950

AC:

1043

AN:

1097868

Hom.:

Cov.:

AF XY:

0.000878

AC XY:

319

AN XY:

363250

show subpopulations

Gnomad4 AFR exome

AF:

0.000152

Gnomad4 AMR exome

AF:

0.000938

Gnomad4 ASJ exome

AF:

0.0000516

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000370

Gnomad4 FIN exome

AF:

0.000395

Gnomad4 NFE exome

AF:

0.00113

Gnomad4 OTH exome

AF:

0.000803

GnomAD4 genome

AF:

0.000635

AC:

AN:

111877

Hom.:

Cov.:

AF XY:

0.000558

AC XY:

AN XY:

34063

show subpopulations

Gnomad4 AFR

AF:

0.000162

Gnomad4 AMR

AF:

0.000666

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000331

Gnomad4 NFE

AF:

0.00105

Gnomad4 OTH

AF:

0.000661

Alfa

AF:

0.00101

Hom.:

Bravo

AF:

0.000691

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00104

AC:

ExAC

AF:

0.000642

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 17, 2018	- -

Chondrodysplasia punctata 2 X-linked dominant

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 26, 2015

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. -

EBP-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 01, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.043

BayesDel_noAF

Uncertain

0.11

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

FATHMM_MKL

Benign

0.56

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.33

MetaRNN

Benign

0.13

MetaSVM

Uncertain

0.70

MutationAssessor

Uncertain

2.7

MutationTaster

Benign

1.0

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-3.3

REVEL

Uncertain

0.48

Sift

Uncertain

0.0020

Sift4G

Benign

0.18

Polyphen

1.0

Vest4

0.17

MVP

0.95

MPC

1.8

ClinPred

0.088

GERP RS

2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.51

gMVP

0.83

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