X-48528275-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM1BP4_ModerateBS1_SupportingBS2

The NM_006579.3(EBP):c.511C>T(p.Arg171Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000921 in 1,209,745 control chromosomes in the GnomAD database, including 2 homozygotes. There are 338 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R171H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00063 ( 0 hom., 19 hem., cov: 23)

Exomes 𝑓: 0.00095 ( 2 hom. 319 hem. )

Consequence

EBP
NM_006579.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1B:7

Conservation

PhyloP100: 2.73

Publications

6 publications found

Variant links:

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

EBP links:

ENSG00000286268 (HGNC:):

ENSG00000286268 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

PM1

In a domain EXPERA (size 143) in uniprot entity EBP_HUMAN there are 27 pathogenic changes around while only 10 benign (73%) in NM_006579.3

BP4

Computational evidence support a benign effect (MetaRNN=0.13119799).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000635 (71/111877) while in subpopulation NFE AF = 0.00105 (56/53200). AF 95% confidence interval is 0.000832. There are 0 homozygotes in GnomAd4. There are 19 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Hemizygotes in GnomAd4 at 19 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.511C>T	p.Arg171Cys	missense	Exon 5 of 5	NP_006570.1	Q15125

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EBP	ENST00000495186.6	TSL:1 MANE Select	c.511C>T	p.Arg171Cys	missense	Exon 5 of 5	ENSP00000417052.1	Q15125
ENSG00000286268	ENST00000651615.1		c.469+990C>T		intron	N/A	ENSP00000498524.1	A0A494C0F3
EBP	ENST00000882073.1		c.511C>T	p.Arg171Cys	missense	Exon 6 of 6	ENSP00000552132.1

Frequencies

GnomAD3 genomes

AF:

0.000635

AC:

AN:

111825

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000162

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000667

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000331

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00105

Gnomad OTH

AF:

0.000670

GnomAD2 exomes

AF:

0.000641

AC:

116

AN:

180993

AF XY:

0.000624

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000951

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000189

Gnomad NFE exome

AF:

0.00102

Gnomad OTH exome

AF:

0.000670

GnomAD4 exome

AF:

0.000950

AC:

1043

AN:

1097868

Hom.:

Cov.:

AF XY:

0.000878

AC XY:

319

AN XY:

363250

show subpopulations

African (AFR)

AF:

0.000152

AC:

AN:

26396

American (AMR)

AF:

0.000938

AC:

AN:

35194

Ashkenazi Jewish (ASJ)

AF:

0.0000516

AC:

AN:

19374

East Asian (EAS)

AF:

0.00

AC:

AN:

30199

South Asian (SAS)

AF:

0.0000370

AC:

AN:

54020

European-Finnish (FIN)

AF:

0.000395

AC:

AN:

40511

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.00113

AC:

950

AN:

841958

Other (OTH)

AF:

0.000803

AC:

AN:

46081

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

115

154

192

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000635

AC:

AN:

111877

Hom.:

Cov.:

AF XY:

0.000558

AC XY:

AN XY:

34063

show subpopulations

African (AFR)

AF:

0.000162

AC:

AN:

30849

American (AMR)

AF:

0.000666

AC:

AN:

10512

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2645

East Asian (EAS)

AF:

0.00

AC:

AN:

3550

South Asian (SAS)

AF:

0.00

AC:

AN:

2665

European-Finnish (FIN)

AF:

0.000331

AC:

AN:

6045

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.00105

AC:

AN:

53200

Other (OTH)

AF:

0.000661

AC:

AN:

1512

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000943

Hom.:

Bravo

AF:

0.000691

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00104

AC:

ExAC

AF:

0.000642

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Chondrodysplasia punctata 2 X-linked dominant (2)

EBP-related disorder (1)

MEND syndrome (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.043

BayesDel_noAF

Uncertain

0.11

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

FATHMM_MKL

Benign

0.56

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.33

MetaRNN

Benign

0.13

MetaSVM

Uncertain

0.70

MutationAssessor

Uncertain

2.7

PhyloP100

2.7

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-3.3

REVEL

Uncertain

0.48

Sift

Uncertain

0.0020

Sift4G

Benign

0.18

Polyphen

1.0

Vest4

0.17

MVP

0.95

MPC

1.8

ClinPred

0.088

GERP RS

2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.51

gMVP

0.83

Mutation Taster

=99/1

disease causing (ClinVar)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over