rs77132068

Positions:

• chr13-77903179-C-A
• chr13-77903179-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001122659.3(EDNRB):​c.778G>T​(p.Val260Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00152 in 1,612,630 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V260I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (2 hom.)
• Consequence: EDNRB NM_001122659.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 0.0800

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:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016279012).
• BP6: Variant 13-77903179-C-A is Benign according to our data. Variant chr13-77903179-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 585146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-77903179-C-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDNRB	NM_001122659.3	c.778G>T	p.Val260Phe	missense_variant	3/7	ENST00000646607.2
EDNRB-AS1	NR_103853.1	n.1695-4513C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDNRB	ENST00000646607.2	c.778G>T	p.Val260Phe	missense_variant	3/7		NM_001122659.3	P1

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 179 AN: 151734 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000315

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00237

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00190

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000845 AC: 212 AN: 250858 Hom.: 2 AF XY: 0.000892 AC XY: 121 AN XY: 135596

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.00144

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00156 AC: 2273 AN: 1460778 Hom.: 2 Cov.: 32 AF XY: 0.00148 AC XY: 1079 AN XY: 726724

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.00101

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.00193

Gnomad4 OTH exome AF: 0.00108

GnomAD4 genome AF: 0.00118 AC: 179 AN: 151852 Hom.: 0 Cov.: 32 AF XY: 0.00119 AC XY: 88 AN XY: 74216

Gnomad4 AFR AF: 0.000314

Gnomad4 AMR AF: 0.00236

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.00190

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00173 Hom.: 1

Bravo AF: 0.00125

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.000749 AC: 91

EpiCase AF: 0.000819

EpiControl AF: 0.00101

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 10, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 02, 2021	This variant is associated with the following publications: (PMID: 20127975, 17223014, 16145050) -

ABCD syndrome;C1838564:Hirschsprung disease, susceptibility to, 2;C1848519:Waardenburg syndrome type 4A Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	1.3
DANN	Benign	0.20
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.089	N
LIST_S2	Benign	0.81	T;.;.;.;.;T;T;T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.016	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.0	N;.;.;N;.;.;.;.;.
REVEL	Benign	0.057
Sift	Benign	0.66	T;.;.;T;.;.;.;.;.
Sift4G	Benign	0.28	T;.;.;T;.;T;.;.;.
Polyphen		0.0010	B;B;B;B;B;B;B;.;.
Vest4		0.18
MVP		0.49
MPC		0.62
ClinPred		0.0021	T
GERP RS		0.29
Varity_R		0.092
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs77132068; hg19: chr13-78477314;