NM_001122659.3:c.203C>G

Variant names:

• chr13-77918371-G-C
• rs201737510
• NM_001122659.3:c.203C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001122659.3(EDNRB):​c.203C>G​(p.Pro68Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. P68L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: EDNRB NM_001122659.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.51
• Publications: 0 publications found

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: AD, AR, SD Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, PanelApp Australia, Ambry Genetics
• 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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13710147).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001122659.3. 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
	EDNRB	NM_001122659.3	MANE Select	c.203C>G	p.Pro68Arg	missense	Exon 1 of 7	NP_001116131.1	P24530-1
	EDNRB	NM_001201397.2		c.473C>G	p.Pro158Arg	missense	Exon 2 of 8	NP_001188326.1	P24530-3
	EDNRB	NM_000115.5		c.203C>G	p.Pro68Arg	missense	Exon 2 of 8	NP_000106.1	P24530-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDNRB	ENST00000646607.2	MANE Select	c.203C>G	p.Pro68Arg	missense	Exon 1 of 7	ENSP00000493527.1	P24530-1
	EDNRB	ENST00000377211.8	TSL:1	c.473C>G	p.Pro158Arg	missense	Exon 2 of 8	ENSP00000366416.4	P24530-3
	EDNRB	ENST00000626030.1	TSL:1	c.203C>G	p.Pro68Arg	missense	Exon 1 of 7	ENSP00000486202.1	P24530-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.5
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.059
Sift	Benign	0.032	D
Sift4G	Uncertain	0.013	D
Polyphen		0.030	B
Vest4		0.30
MutPred		0.40		Gain of MoRF binding (P = 4e-04)
MVP		0.81
MPC		0.49
ClinPred		0.61	D
GERP RS		2.9
PromoterAI		-0.077	Neutral
Varity_R		0.095
gMVP		0.36
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

Other links and lift over

dbSNP: rs201737510; hg19: chr13-78492506;