X-48523553-G-GA

Variant names:

• chrX-48523553-G-GA
• rs782437115
• NM_006579.3:c.-73-129dupA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_006579.3(EBP):​c.-73-129dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.235 in 220,936 control chromosomes in the GnomAD database, including 63 homozygotes. There are 310 hemizygotes in GnomAD. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.054 (55 hom., 254 hem., cov: 19)
  • Exomes 𝑓: 0.28 (8 hom. 56 hem.)
• Consequence: EBP NM_006579.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.234
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant X-48523553-G-GA is Benign according to our data. Variant chrX-48523553-G-GA is described in ClinVar as Benign. ClinVar VariationId is 1293795.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.071 is higher than 0.05.

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.-73-129dupA		intron	N/A	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.-73-129dupA		intron	N/A	ENSP00000417052.1	Q15125
	ENSG00000286268	ENST00000651615.1		c.-73-129dupA		intron	N/A	ENSP00000498524.1	A0A494C0F3
	EBP	ENST00000882083.1		c.-202dupA		5_prime_UTR	Exon 1 of 4	ENSP00000552142.1

Frequencies

GnomAD3 genomes AF: 0.0539 AC: 2493 AN: 46256 Hom.: 55 Cov.: 19

Gnomad AFR AF: 0.00869

Gnomad AMI AF: 0.345

Gnomad AMR AF: 0.0343

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.0112

Gnomad SAS AF: 0.0137

Gnomad FIN AF: 0.0649

Gnomad MID AF: 0.0556

Gnomad NFE AF: 0.0738

Gnomad OTH AF: 0.0642

GnomAD4 exome AF: 0.283 AC: 49368 AN: 174674 Hom.: 8 AF XY: 0.00209 AC XY: 56 AN XY: 26822

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.281 AC: 1576 AN: 5609

American (AMR) AF: 0.305 AC: 2637 AN: 8641

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 1395 AN: 4844

East Asian (EAS) AF: 0.279 AC: 2885 AN: 10328

South Asian (SAS) AF: 0.227 AC: 2988 AN: 13192

European-Finnish (FIN) AF: 0.296 AC: 2929 AN: 9911

Middle Eastern (MID) AF: 0.266 AC: 170 AN: 638

European-Non Finnish (NFE) AF: 0.287 AC: 31862 AN: 111176

Other (OTH) AF: 0.283 AC: 2926 AN: 10335

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0539 AC: 2492 AN: 46262 Hom.: 55 Cov.: 19 AF XY: 0.0287 AC XY: 254 AN XY: 8856

African (AFR) AF: 0.00868 AC: 105 AN: 12094

American (AMR) AF: 0.0340 AC: 117 AN: 3442

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 156 AN: 1367

East Asian (EAS) AF: 0.0112 AC: 14 AN: 1248

South Asian (SAS) AF: 0.0138 AC: 12 AN: 870

European-Finnish (FIN) AF: 0.0649 AC: 74 AN: 1141

Middle Eastern (MID) AF: 0.0588 AC: 4 AN: 68

European-Non Finnish (NFE) AF: 0.0738 AC: 1854 AN: 25127

Other (OTH) AF: 0.0632 AC: 35 AN: 554

Alfa AF: 0.00715 Hom.: 24

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.23
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs782437115; hg19: chrX-48381941;