rs142881014

Variant names:

• chrX-48527198-C-T
• rs142881014
• NM_006579.3:c.382C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_006579.3(EBP):​c.382C>T​(p.Leu128Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00129 in 1,210,037 control chromosomes in the GnomAD database, including 4 homozygotes. There are 539 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0028 (0 hom., 93 hem., cov: 23)
  • Exomes 𝑓: 0.0011 (4 hom. 446 hem.)
• Consequence: EBP NM_006579.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.137
• Publications: 2 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: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp
• X-linked chondrodysplasia punctata 2

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

ENSG00000286268 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant X-48527198-C-T is Benign according to our data. Variant chrX-48527198-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 158547.
• BP7: Synonymous conserved (PhyloP=0.137 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00281 (314/111790) while in subpopulation AFR AF = 0.00654 (201/30757). AF 95% confidence interval is 0.0058. There are 0 homozygotes in GnomAd4. There are 93 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 93 XL gene

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.382C>T	p.Leu128Leu	synonymous	Exon 4 of 5	NP_006570.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EBP	ENST00000495186.6	TSL:1 MANE Select	c.382C>T	p.Leu128Leu	synonymous	Exon 4 of 5	ENSP00000417052.1
	ENSG00000286268	ENST00000651615.1		c.382C>T	p.Leu128Leu	synonymous	Exon 4 of 7	ENSP00000498524.1
	EBP	ENST00000882073.1		c.382C>T	p.Leu128Leu	synonymous	Exon 5 of 6	ENSP00000552132.1

Frequencies

GnomAD3 genomes AF: 0.00284 AC: 317 AN: 111737 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00665

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.00642

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000772

Gnomad OTH AF: 0.00598

GnomAD2 exomes AF: 0.00205 AC: 376 AN: 183484 AF XY: 0.00183

Gnomad AFR exome AF: 0.00699

Gnomad AMR exome AF: 0.00405

Gnomad ASJ exome AF: 0.00961

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000952

Gnomad OTH exome AF: 0.00507

GnomAD4 exome AF: 0.00114 AC: 1252 AN: 1098247 Hom.: 4 Cov.: 31 AF XY: 0.00123 AC XY: 446 AN XY: 363601

African (AFR) AF: 0.00720 AC: 190 AN: 26402

American (AMR) AF: 0.00395 AC: 139 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00810 AC: 157 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.0000554 AC: 3 AN: 54146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40529

Middle Eastern (MID) AF: 0.00556 AC: 23 AN: 4136

European-Non Finnish (NFE) AF: 0.000684 AC: 576 AN: 842138

Other (OTH) AF: 0.00356 AC: 164 AN: 46097

GnomAD4 genome AF: 0.00281 AC: 314 AN: 111790 Hom.: 0 Cov.: 23 AF XY: 0.00274 AC XY: 93 AN XY: 33974

African (AFR) AF: 0.00654 AC: 201 AN: 30757

American (AMR) AF: 0.00406 AC: 43 AN: 10596

Ashkenazi Jewish (ASJ) AF: 0.00642 AC: 17 AN: 2646

East Asian (EAS) AF: 0.00 AC: 0 AN: 3519

South Asian (SAS) AF: 0.00 AC: 0 AN: 2625

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6146

Middle Eastern (MID) AF: 0.0139 AC: 3 AN: 216

European-Non Finnish (NFE) AF: 0.000772 AC: 41 AN: 53078

Other (OTH) AF: 0.00591 AC: 9 AN: 1524

Alfa AF: 0.00334 Hom.: 15

Bravo AF: 0.00411

EpiCase AF: 0.00169

EpiControl AF: 0.00148

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	1	-	Chondrodysplasia punctata 2 X-linked dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.1
DANN	Benign	0.59
PhyloP100		0.14
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: rs142881014; hg19: chrX-48385586;