NM_001122659.3:c.731C>G

Variant names:

• chr13-77903226-G-C
• rs5350
• NM_001122659.3:c.731C>G

Variant summary

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

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. 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.78
• 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-AS1 (HGNC:49045): (EDNRB antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDNRB	NM_001122659.3	c.731C>G	p.Thr244Arg	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.731C>G	p.Thr244Arg	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

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;.;.
PhyloP100		1.8
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
PromoterAI		-0.021	Neutral
Varity_R		0.25
gMVP		0.90
Mutation Taster		=80/20	polymorphism

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

Other links and lift over

dbSNP: rs5350; hg19: chr13-78477361;