X-48523553-GAAAAA-GAAA

Variant names:

• chrX-48523553-GAA-G
• rs782437115
• NM_006579.3:c.-73-130_-73-129delAA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_006579.3(EBP):​c.-73-130_-73-129delAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00338 in 268,458 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000086 (0 hom., 0 hem., cov: 19)
  • Exomes 𝑓: 0.0041 (0 hom. 1 hem.)
• Consequence: EBP NM_006579.3 intron
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000859 (4/46569) while in subpopulation AMR AF = 0.000578 (2/3458). AF 95% confidence interval is 0.000103. There are 0 homozygotes in GnomAd4. There are 0 alleles in the male GnomAd4 subpopulation. Median coverage is 19. This position passed quality control check.

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.-73-130_-73-129delAA		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.-73-130_-73-129delAA		intron	N/A	ENSP00000417052.1	Q15125
	ENSG00000286268	ENST00000651615.1		c.-73-130_-73-129delAA		intron	N/A	ENSP00000498524.1	A0A494C0F3
	EBP	ENST00000882083.1		c.-203_-202delAA		5_prime_UTR	Exon 1 of 4	ENSP00000552142.1

Frequencies

GnomAD3 genomes AF: 0.0000859 AC: 4 AN: 46563 Hom.: 0 Cov.: 19

Gnomad AFR AF: 0.000165

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000579

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00407 AC: 904 AN: 221889 Hom.: 0 AF XY: 0.0000143 AC XY: 1 AN XY: 69753

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

African (AFR) AF: 0.00572 AC: 38 AN: 6646

American (AMR) AF: 0.00338 AC: 36 AN: 10654

Ashkenazi Jewish (ASJ) AF: 0.00651 AC: 39 AN: 5992

East Asian (EAS) AF: 0.00482 AC: 60 AN: 12447

South Asian (SAS) AF: 0.00108 AC: 25 AN: 23191

European-Finnish (FIN) AF: 0.00458 AC: 55 AN: 12010

Middle Eastern (MID) AF: 0.00493 AC: 4 AN: 812

European-Non Finnish (NFE) AF: 0.00423 AC: 582 AN: 137527

Other (OTH) AF: 0.00515 AC: 65 AN: 12610

⚠️ 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: 0.0000859 AC: 4 AN: 46569 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 8909

African (AFR) AF: 0.000165 AC: 2 AN: 12158

American (AMR) AF: 0.000578 AC: 2 AN: 3458

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1378

East Asian (EAS) AF: 0.00 AC: 0 AN: 1258

South Asian (SAS) AF: 0.00 AC: 0 AN: 874

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1146

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 68

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 25312

Other (OTH) AF: 0.00 AC: 0 AN: 562

Alfa AF: 0.00 Hom.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.23

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

Other links and lift over

dbSNP: rs782437115; hg19: chrX-48381941;