X-48523848-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1 BP4_Moderate BS2

The NM_006579.3(EBP):c.77G>A(p.Arg26His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000613 in 1,207,326 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 18 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000037 (0 hom., 1 hem., cov: 21)
  • Exomes 𝑓: 0.000064 (0 hom. 17 hem.)
• Consequence: EBP NM_006579.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.00600

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 Likely_benign. Variant got -4 ACMG points.

• PM1: In a chain 3-beta-hydroxysteroid-Delta(8),Delta(7)-isomerase (size 228) in uniprot entity EBP_HUMAN there are 35 pathogenic changes around while only 14 benign (71%) in NM_006579.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.072814316).
• BS2: High Hemizygotes in GnomAdExome at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EBP	NM_006579.3	c.77G>A	p.Arg26His	missense_variant	2/5	ENST00000495186.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EBP	ENST00000495186.6	c.77G>A	p.Arg26His	missense_variant	2/5	1	NM_006579.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000366 AC: 4 AN: 109204 Hom.: 0 Cov.: 21 AF XY: 0.0000315 AC XY: 1 AN XY: 31716

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000291

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000570

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000709 AC: 13 AN: 183334 Hom.: 0 AF XY: 0.0000738 AC XY: 5 AN XY: 67774

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.000577

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000367

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000637 AC: 70 AN: 1098122 Hom.: 0 Cov.: 34 AF XY: 0.0000468 AC XY: 17 AN XY: 363476

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.0000516

Gnomad4 EAS exome AF: 0.000132

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000724

Gnomad4 OTH exome AF: 0.0000434

GnomAD4 genome AF: 0.0000366 AC: 4 AN: 109204 Hom.: 0 Cov.: 21 AF XY: 0.0000315 AC XY: 1 AN XY: 31716

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000291

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000570

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000680

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.000327

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 26, 2023

This variant has not been reported in the literature in individuals affected with EBP-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 26 of the EBP protein (p.Arg26His). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	0.36
Dann	Benign	0.81
DEOGEN2	Benign	0.41	T;T;.
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.52	T;T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.073	T;T;T
MetaSVM	Uncertain	0.15	D
MutationAssessor	Benign	1.6	L;.;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Uncertain	0.35
Sift	Benign	0.54	T;T;T
Sift4G	Benign	0.54	T;T;T
Polyphen		0.66	P;.;.
Vest4		0.047
MVP		0.84
MPC		0.88
ClinPred		0.034	T
GERP RS		-8.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.060
gMVP		0.77

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

Other links and lift over

dbSNP: rs782358140; hg19: chrX-48382236; COSMIC: COSV52141525; COSMIC: COSV52141525;