X-48523796-C-G

Variant names:

• chrX-48523796-C-G
• NM_006579.3:c.25C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006579.3(EBP):​c.25C>G​(p.His9Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000000912 in 1,096,434 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H9Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: EBP NM_006579.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.36
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• chondrodysplasia punctata 2, X-linked dominant

  Inheritance: XL Classification: DEFINITIVE Submitted by: Illumina
• MEND syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, ClinGen
• X-linked chondrodysplasia punctata 2

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P

ENSG00000286268 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.931

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006579.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EBP	NM_006579.3	MANE Select	c.25C>G	p.His9Asp	missense	Exon 2 of 5	NP_006570.1	Q15125

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EBP	ENST00000495186.6	TSL:1 MANE Select	c.25C>G	p.His9Asp	missense	Exon 2 of 5	ENSP00000417052.1	Q15125
	ENSG00000286268	ENST00000651615.1		c.25C>G	p.His9Asp	missense	Exon 2 of 7	ENSP00000498524.1	A0A494C0F3
	EBP	ENST00000882073.1		c.25C>G	p.His9Asp	missense	Exon 3 of 6	ENSP00000552132.1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1096434 Hom.: 0 Cov.: 34 AF XY: 0.00000276 AC XY: 1 AN XY: 361916

African (AFR) AF: 0.00 AC: 0 AN: 26378

American (AMR) AF: 0.00 AC: 0 AN: 35010

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19352

East Asian (EAS) AF: 0.00 AC: 0 AN: 30134

South Asian (SAS) AF: 0.00 AC: 0 AN: 53882

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40414

Middle Eastern (MID) AF: 0.000243 AC: 1 AN: 4109

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841126

Other (OTH) AF: 0.00 AC: 0 AN: 46029

GnomAD4 genome Cov.: 21

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.70	D
BayesDel_noAF	Pathogenic	0.77
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.73	T
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		6.4
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.69		Loss of glycosylation at P7 (P = 0.1241)
MVP		1.0
MPC		1.9
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		1.0
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chrX-48382184;