chr13-77903179-C-T

Variant names:

• chr13-77903179-C-T
• rs77132068
• NM_001122659.3:c.778G>A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_001122659.3(EDNRB):​c.778G>A​(p.Val260Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000207 in 1,612,630 control chromosomes in the GnomAD database, including 1 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V260F) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (1 hom.)
• Consequence: EDNRB NM_001122659.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• 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:49045): (EDNRB antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.038647383).
• BP6: Variant 13-77903179-C-T is Benign according to our data. Variant chr13-77903179-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 504853.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}. Variant chr13-77903179-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000165 (25/151854) while in subpopulation SAS AF= 0.000416 (2/4802). AF 95% confidence interval is 0.000195. There are 0 homozygotes in gnomad4. There are 16 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDNRB	NM_001122659.3	c.778G>A	p.Val260Ile	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.778G>A	p.Val260Ile	missense_variant	Exon 3 of 7		NM_001122659.3	ENSP00000493527.1

Frequencies

GnomAD3 genomes AF: 0.000165 AC: 25 AN: 151736 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000295

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000147 AC: 37 AN: 250858 Hom.: 1 AF XY: 0.000199 AC XY: 27 AN XY: 135596

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000168

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000212 AC: 309 AN: 1460776 Hom.: 1 Cov.: 32 AF XY: 0.000237 AC XY: 172 AN XY: 726722

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.000452

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000222

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000165 AC: 25 AN: 151854 Hom.: 0 Cov.: 32 AF XY: 0.000216 AC XY: 16 AN XY: 74218

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000295

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.0000144 Hom.: 1

Bravo AF: 0.000147

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ExAC AF: 0.000165 AC: 20

EpiCase AF: 0.000273

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Feb 03, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 21507037) -

Oct 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

EDNRB: BP4 -

Hirschsprung disease, susceptibility to, 2 Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Benign:1

Dec 14, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Val350Ile in exon 4 of EDNRB: This variant is not expected to have clinical si gnificance due to a lack of conservation across species, including mammals. Of n ote, at least 6 mammals have an isoleucine (Ile) at this position despite high n earby amino acid conservation. In addition, computational prediction tools do no t suggest a high likelihood of impact to the protein. This variant has been iden tified in 0.05% (14/30780) of South Asian chromosomes, including one homozygote, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; d bSNP rs77132068). ACMG/AMP Criteria applied: BP4_Strong -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	1.1
DANN	Benign	0.71
DEOGEN2	Benign	0.29	.;T;T;T;T;.;T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.76	T;.;.;.;.;T;T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.039	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.32	.;N;N;N;N;N;N;.;.
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.37	N;.;.;N;.;.;.;.;.
REVEL	Benign	0.058
Sift	Benign	0.33	T;.;.;T;.;.;.;.;.
Sift4G	Benign	0.26	T;.;.;T;.;T;.;.;.
Polyphen		0.0020	B;B;B;B;B;B;B;.;.
Vest4		0.079
MVP		0.34
MPC		0.37
ClinPred		0.0034	T
GERP RS		0.29
Varity_R		0.022
gMVP		0.46

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

LitVar

Other links and lift over

dbSNP: rs77132068; hg19: chr13-78477314; COSMIC: COSV57521919;