13-77903226-G-C

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

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.731C>G	p.Thr244Arg	missense	Exon 3 of 7	NP_001116131.1	P24530-1
	EDNRB	NM_001201397.2		c.1001C>G	p.Thr334Arg	missense	Exon 4 of 8	NP_001188326.1	P24530-3
	EDNRB	NM_000115.5		c.731C>G	p.Thr244Arg	missense	Exon 4 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.731C>G	p.Thr244Arg	missense	Exon 3 of 7	ENSP00000493527.1	P24530-1
	EDNRB	ENST00000377211.8	TSL:1	c.1001C>G	p.Thr334Arg	missense	Exon 4 of 8	ENSP00000366416.4	P24530-3
	EDNRB	ENST00000626030.1	TSL:1	c.731C>G	p.Thr244Arg	missense	Exon 3 of 7	ENSP00000486202.1	P24530-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.48
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.045	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	2.0	M
PhyloP100		1.8
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.37
Sift	Benign	0.16	T
Sift4G	Benign	0.19	T
Polyphen		0.36	B
Vest4		0.57
MutPred		0.57		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;