chr13-77918371-G-A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001122659.3(EDNRB):​c.203C>T​(p.Pro68Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000023 in 1,608,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P68R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

EDNRB
NM_001122659.3 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.51

Publications

0 publications found
Variant links:
Genes affected
EDNRB (HGNC:3180): (endothelin receptor type B) The protein encoded by this gene is a G protein-coupled receptor which activates a phosphatidylinositol-calcium second messenger system. Its ligand, endothelin, consists of a family of three potent vasoactive peptides: ET1, ET2, and ET3. Studies suggest that the multigenic disorder, Hirschsprung disease type 2, is due to mutations in the endothelin receptor type B gene. Alternative splicing and the use of alternative promoters results in multiple transcript variants. [provided by RefSeq, Oct 2016]
EDNRB Gene-Disease associations (from GenCC):
  • ABCD syndrome
    Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
  • Waardenburg syndrome type 4A
    Inheritance: AR, AD, SD Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: PanelApp Australia, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
  • Waardenburg syndrome type 2
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • Waardenburg-Shah syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • Hirschsprung disease, susceptibility to, 2
    Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.12322599).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EDNRBNM_001122659.3 linkc.203C>T p.Pro68Leu missense_variant Exon 1 of 7 ENST00000646607.2 NP_001116131.1 P24530-1
EDNRBNM_001201397.2 linkc.473C>T p.Pro158Leu missense_variant Exon 2 of 8 NP_001188326.1 P24530-3A0A024R638
EDNRBNM_000115.5 linkc.203C>T p.Pro68Leu missense_variant Exon 2 of 8 NP_000106.1 P24530-1
EDNRBNM_003991.4 linkc.203C>T p.Pro68Leu missense_variant Exon 1 of 7 NP_003982.1 P24530-2A0A024R645

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
EDNRBENST00000646607.2 linkc.203C>T p.Pro68Leu missense_variant Exon 1 of 7 NM_001122659.3 ENSP00000493527.1 P24530-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152108
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000294
Gnomad OTH
AF:
0.000478
GnomAD4 exome
AF:
0.0000233
AC:
34
AN:
1456810
Hom.:
0
Cov.:
31
AF XY:
0.0000235
AC XY:
17
AN XY:
723814
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33270
American (AMR)
AF:
0.00
AC:
0
AN:
44410
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25964
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39592
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86038
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53330
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5750
European-Non Finnish (NFE)
AF:
0.0000280
AC:
31
AN:
1108336
Other (OTH)
AF:
0.0000499
AC:
3
AN:
60120
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.496
Heterozygous variant carriers
0
3
6
10
13
16
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000197
AC:
3
AN:
152108
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
74280
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41436
American (AMR)
AF:
0.00
AC:
0
AN:
15270
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5152
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4822
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10610
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000294
AC:
2
AN:
68028
Other (OTH)
AF:
0.000478
AC:
1
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.542
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.00
Hom.:
0
Bravo
AF:
0.0000113

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Aug 02, 2016
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Pro158Leu var iant in EDNRB has not been previously reported in individuals with hearing loss, Waardenburg syndrome, or Hirschsprung disease, or in large population studies. The proline (Pro) at position 158 is not conserved across species, including ma mmals. Of note, two mammals (elephant and manatee) have a leucine (Leu) at this position despite high nearby amino acid sequence conservation. Additional comp utational prediction tools suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the p.Pro158Leu variant is uncertain , these data suggest it is more likely to be benign. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.073
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Benign
-0.44
CADD
Benign
22
DANN
Uncertain
0.98
DEOGEN2
Benign
0.34
.;T;T;T;T;.;T;.
Eigen
Benign
-0.59
Eigen_PC
Benign
-0.57
FATHMM_MKL
Benign
0.28
N
LIST_S2
Benign
0.63
T;.;.;.;.;T;T;T
M_CAP
Benign
0.038
D
MetaRNN
Benign
0.12
T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.95
T
MutationAssessor
Uncertain
2.2
.;M;M;M;M;M;M;.
PhyloP100
2.5
PrimateAI
Benign
0.27
T
PROVEAN
Benign
-1.0
N;.;.;N;.;.;.;.
REVEL
Benign
0.068
Sift
Benign
0.18
T;.;.;T;.;.;.;.
Sift4G
Uncertain
0.010
D;.;.;T;.;D;.;.
Polyphen
0.0070
B;B;B;B;B;B;B;.
Vest4
0.097
MutPred
0.33
.;Loss of glycosylation at S65 (P = 0.0954);Loss of glycosylation at S65 (P = 0.0954);Loss of glycosylation at S65 (P = 0.0954);Loss of glycosylation at S65 (P = 0.0954);Loss of glycosylation at S65 (P = 0.0954);Loss of glycosylation at S65 (P = 0.0954);Loss of glycosylation at S65 (P = 0.0954);
MVP
0.78
MPC
0.47
ClinPred
0.64
D
GERP RS
2.9
PromoterAI
0.13
Neutral
Varity_R
0.081
gMVP
0.30
Mutation Taster
=81/19
polymorphism

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

Other links and lift over

dbSNP: rs201737510; hg19: chr13-78492506; API