X-48523786-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006579.3(EBP):c.15G>T(p.Ala5=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.337 in 1,195,442 control chromosomes in the GnomAD database, including 47,684 homozygotes. There are 128,731 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A5A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.29 (3804 hom., 6833 hem., cov: 19)
  • Exomes 𝑓: 0.34 (43880 hom. 121898 hem.)
• Consequence: EBP NM_006579.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.544

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant X-48523786-G-T is Benign according to our data. Variant chrX-48523786-G-T is described in ClinVar as [Benign]. Clinvar id is 158531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.544 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.37 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EBP	NM_006579.3	c.15G>T	p.Ala5=	synonymous_variant	2/5	ENST00000495186.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EBP	ENST00000495186.6	c.15G>T	p.Ala5=	synonymous_variant	2/5	1	NM_006579.3	P1

Frequencies

GnomAD3 genomes AF: 0.291 AC: 29826 AN: 102490 Hom.: 3798 Cov.: 19 AF XY: 0.263 AC XY: 6832 AN XY: 26020

Gnomad AFR AF: 0.189

Gnomad AMI AF: 0.283

Gnomad AMR AF: 0.308

Gnomad ASJ AF: 0.197

Gnomad EAS AF: 0.388

Gnomad SAS AF: 0.284

Gnomad FIN AF: 0.369

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.337

Gnomad OTH AF: 0.270

GnomAD3 exomes AF: 0.330 AC: 56135 AN: 170094 Hom.: 6532 AF XY: 0.325 AC XY: 18447 AN XY: 56688

Gnomad AFR exome AF: 0.196

Gnomad AMR exome AF: 0.346

Gnomad ASJ exome AF: 0.192

Gnomad EAS exome AF: 0.413

Gnomad SAS exome AF: 0.300

Gnomad FIN exome AF: 0.407

Gnomad NFE exome AF: 0.339

Gnomad OTH exome AF: 0.305

GnomAD4 exome AF: 0.341 AC: 373162 AN: 1092919 Hom.: 43880 Cov.: 36 AF XY: 0.339 AC XY: 121898 AN XY: 359315

Gnomad4 AFR exome AF: 0.193

Gnomad4 AMR exome AF: 0.345

Gnomad4 ASJ exome AF: 0.191

Gnomad4 EAS exome AF: 0.437

Gnomad4 SAS exome AF: 0.301

Gnomad4 FIN exome AF: 0.406

Gnomad4 NFE exome AF: 0.348

Gnomad4 OTH exome AF: 0.312

GnomAD4 genome AF: 0.291 AC: 29837 AN: 102523 Hom.: 3804 Cov.: 19 AF XY: 0.262 AC XY: 6833 AN XY: 26065

Gnomad4 AFR AF: 0.189

Gnomad4 AMR AF: 0.309

Gnomad4 ASJ AF: 0.197

Gnomad4 EAS AF: 0.388

Gnomad4 SAS AF: 0.282

Gnomad4 FIN AF: 0.369

Gnomad4 NFE AF: 0.337

Gnomad4 OTH AF: 0.267

Alfa AF: 0.303 Hom.: 9860

Bravo AF: 0.290

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 29, 2016	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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Chondrodysplasia punctata 2 X-linked dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

MEND syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	1.4
Dann	Benign	0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs3048; hg19: chrX-48382174; COSMIC: COSV52141291; COSMIC: COSV52141291;