13-77903226-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_001122659.3(EDNRB):​c.731C>G​(p.Thr244Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T244M) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

EDNRB
NM_001122659.3 missense

Scores

6
13

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.78
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-AS1 (HGNC:49045): (EDNRB antisense RNA 1)

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1
In a disulfide_bond (size 81) in uniprot entity EDNRB_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_001122659.3
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EDNRBNM_001122659.3 linkc.731C>G p.Thr244Arg missense_variant Exon 3 of 7 ENST00000646607.2 NP_001116131.1 P24530-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
EDNRBENST00000646607.2 linkc.731C>G p.Thr244Arg missense_variant Exon 3 of 7 NM_001122659.3 ENSP00000493527.1 P24530-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.090
BayesDel_addAF
Uncertain
0.013
T
BayesDel_noAF
Benign
-0.22
CADD
Benign
21
DANN
Benign
0.91
DEOGEN2
Uncertain
0.52
.;D;D;D;D;.;D;.;.
Eigen
Benign
-0.42
Eigen_PC
Benign
-0.48
FATHMM_MKL
Uncertain
0.80
D
LIST_S2
Benign
0.85
D;.;.;.;.;D;D;D;D
M_CAP
Benign
0.045
D
MetaRNN
Uncertain
0.53
D;D;D;D;D;D;D;D;D
MetaSVM
Benign
-0.62
T
MutationAssessor
Benign
2.0
.;M;M;M;M;M;M;.;.
PrimateAI
Benign
0.35
T
PROVEAN
Uncertain
-2.5
N;.;.;N;.;.;.;.;.
REVEL
Uncertain
0.37
Sift
Benign
0.16
T;.;.;T;.;.;.;.;.
Sift4G
Benign
0.19
T;.;.;T;.;T;.;.;.
Polyphen
0.36
B;P;P;P;P;D;P;.;.
Vest4
0.57
MutPred
0.57
.;Loss of glycosylation at T244 (P = 0.029);Loss of glycosylation at T244 (P = 0.029);Loss of glycosylation at T244 (P = 0.029);Loss of glycosylation at T244 (P = 0.029);Loss of glycosylation at T244 (P = 0.029);Loss of glycosylation at T244 (P = 0.029);.;Loss of glycosylation at T244 (P = 0.029);
MVP
0.91
MPC
0.69
ClinPred
0.83
D
GERP RS
3.0
Varity_R
0.25
gMVP
0.90

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.15
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-78477361; API