chrX-48524070-T-C

Variant names:

• chrX-48524070-T-C
• rs587783605
• NM_006579.3:c.299T>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_006579.3(EBP):​c.299T>C​(p.Leu100Pro) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L100I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 22)
• Consequence: EBP NM_006579.3 missense, splice_region
• Scores: Splicing: ADA: 0.6294
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.16
• 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: 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_006579.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant X-48524070-T-C is Pathogenic according to our data. Variant chrX-48524070-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 158537.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EBP	NM_006579.3	c.299T>C	p.Leu100Pro	missense_variant, splice_region_variant	Exon 2 of 5	ENST00000495186.6	NP_006570.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EBP	ENST00000495186.6	c.299T>C	p.Leu100Pro	missense_variant, splice_region_variant	Exon 2 of 5	1	NM_006579.3	ENSP00000417052.1
ENSG00000286268	ENST00000651615.1	c.299T>C	p.Leu100Pro	missense_variant, splice_region_variant	Exon 2 of 7			ENSP00000498524.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Chondrodysplasia punctata 2 X-linked dominant Pathogenic:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.72	D
BayesDel_noAF	Pathogenic	0.79
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D;D;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T;D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H;.;.
PhyloP100		7.2
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-6.1	D;D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.94
MutPred		0.94		Loss of stability (P = 0.0111);Loss of stability (P = 0.0111);Loss of stability (P = 0.0111);
MVP		1.0
MPC		2.0
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.99
gMVP		1.0
Mutation Taster		=19/81	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.63
dbscSNV1_RF	Benign	0.61
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: rs587783605; hg19: chrX-48382458;