rs28935174

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_006579.3(EBP):c.440G>A(p.Arg147His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R147G) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 23)

Consequence

EBP
NM_006579.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 8.98

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:

ENSG00000286268 (HGNC:):

ENSG00000286268 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.994

PP5

Variant X-48527256-G-A is Pathogenic according to our data. Variant chrX-48527256-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 11492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-48527256-G-A is described in Lovd as [Pathogenic]. Variant chrX-48527256-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EBP	NM_006579.3 link	c.440G>A	p.Arg147His	missense_variant	Exon 4 of 5	ENST00000495186.6	NP_006570.1	Q15125A0A024QYX0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EBP	ENST00000495186.6 link	c.440G>A	p.Arg147His	missense_variant	Exon 4 of 5	1	NM_006579.3	ENSP00000417052.1		Q15125
ENSG00000286268	ENST00000651615.1 link	c.440G>A	p.Arg147His	missense_variant	Exon 4 of 7			ENSP00000498524.1		A0A494C0F3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Chondrodysplasia punctata 2 X-linked dominant

Pathogenic:4

May 22, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.95; 3Cnet: 0.96). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000011492). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID:10942423, 12483303, 1355069, 24726177, 7677157). Different missense changes at the same codon (p.Arg147Cys, p.Arg147Gly) have been reported to be associated with EBP related disorder (ClinVar ID: VCV000265110 / PMID: 11493318, 26075358). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Pathogenic:1

Sep 22, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Female patient witth this variant showed accumulation of 8(9)-cholesterol and 8-dehydrocholesterol by GC/MS, suggestive of a defect of sterol-delta8-isomerase, and subsequent functional studies showed that this variant partially impairs enzyme activity (Braverman et al., 1999); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11982764, 22121851, 10391219, 7677157, 1355069, 11493318, 25814754, 22229330, 12824059, 12509714, 27276700, 14632217, 12483303, 11038443, 17625999, 19416264, 31299979, 30608402, 10942423, 34450268, SunMA2023[Article]) -

Chondrodysplasia punctata 2 X-linked dominant;C4085243:MEND syndrome

Pathogenic:1

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PP3_Strong+PM5+PS4_Moderate+PS2+PP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Pathogenic

0.72

BayesDel_noAF

Pathogenic

0.79

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

D;D

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.84

T;D

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.3

M;.

PrimateAI

Benign

0.39

PROVEAN

Pathogenic

-4.8

D;D

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

D;.

Vest4

0.93

MutPred

0.97

Loss of methylation at R142 (P = 0.1043);Loss of methylation at R142 (P = 0.1043);

MVP

1.0

MPC

1.8

ClinPred

0.99

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.94

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