NM_001122659.3:c.758G>C

Variant names:

• chr13-77903199-C-G
• NM_001122659.3:c.758G>C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_001122659.3(EDNRB):​c.758G>C​(p.Arg253Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EDNRB NM_001122659.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.73

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)

ACMG classification

Verdict is Uncertain_significance. Variant got 5 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.834

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDNRB	NM_001122659.3	c.758G>C	p.Arg253Pro	missense_variant	Exon 3 of 7	ENST00000646607.2	NP_001116131.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDNRB	ENST00000646607.2	c.758G>C	p.Arg253Pro	missense_variant	Exon 3 of 7		NM_001122659.3	ENSP00000493527.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jan 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.758G>C (p.R253P) alteration is located in exon 4 (coding exon 3) of the EDNRB gene. This alteration results from a G to C substitution at nucleotide position 758, causing the arginine (R) at amino acid position 253 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	.;D;D;D;D;.;D;.;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;.;.;.;.;D;D;D;D
M_CAP	Uncertain	0.093	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	1.9	.;M;M;M;M;M;M;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.9	D;.;.;D;.;.;.;.;.
REVEL	Pathogenic	0.69
Sift	Benign	0.041	D;.;.;T;.;.;.;.;.
Sift4G	Uncertain	0.018	D;.;.;D;.;D;.;.;.
Polyphen		0.92	P;P;P;P;P;D;P;.;.
Vest4		0.84
MutPred		0.63		.;Loss of catalytic residue at R253 (P = 0.0179);Loss of catalytic residue at R253 (P = 0.0179);Loss of catalytic residue at R253 (P = 0.0179);Loss of catalytic residue at R253 (P = 0.0179);Loss of catalytic residue at R253 (P = 0.0179);Loss of catalytic residue at R253 (P = 0.0179);.;Loss of catalytic residue at R253 (P = 0.0179);
MVP		0.94
MPC		0.79
ClinPred		0.97	D
GERP RS		3.9
Varity_R		0.86
gMVP		0.98

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-78477334;