rs5351

Variant names:

• chr13-77901178-T-C
• rs5351
• NM_001122659.3:c.831A>G

Your query was ambiguous. Multiple possible variants found:

• chr13-77901178-T-C
• chr13-77901178-T-G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001122659.3(EDNRB):​c.831A>G​(p.Leu277Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.601 in 1,610,368 control chromosomes in the GnomAD database, including 293,077 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (25616 hom., cov: 32)
  • Exomes 𝑓: 0.60 (267461 hom.)
• Consequence: EDNRB NM_001122659.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.124
• Publications: 59 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 13-77901178-T-C is Benign according to our data. Variant chr13-77901178-T-C is described in ClinVar as Benign. ClinVar VariationId is 226622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.124 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.618 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDNRB	NM_001122659.3	c.831A>G	p.Leu277Leu	synonymous_variant	Exon 4 of 7	ENST00000646607.2	NP_001116131.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDNRB	ENST00000646607.2	c.831A>G	p.Leu277Leu	synonymous_variant	Exon 4 of 7		NM_001122659.3	ENSP00000493527.1

Frequencies

GnomAD3 genomes AF: 0.578 AC: 87644 AN: 151594 Hom.: 25610 Cov.: 32

Gnomad AFR AF: 0.540

Gnomad AMI AF: 0.635

Gnomad AMR AF: 0.566

Gnomad ASJ AF: 0.508

Gnomad EAS AF: 0.348

Gnomad SAS AF: 0.544

Gnomad FIN AF: 0.598

Gnomad MID AF: 0.615

Gnomad NFE AF: 0.623

Gnomad OTH AF: 0.572

GnomAD2 exomes AF: 0.574 AC: 143733 AN: 250254 AF XY: 0.574

Gnomad AFR exome AF: 0.546

Gnomad AMR exome AF: 0.583

Gnomad ASJ exome AF: 0.511

Gnomad EAS exome AF: 0.330

Gnomad FIN exome AF: 0.599

Gnomad NFE exome AF: 0.621

Gnomad OTH exome AF: 0.583

GnomAD4 exome AF: 0.603 AC: 879869 AN: 1458656 Hom.: 267461 Cov.: 48 AF XY: 0.601 AC XY: 436238 AN XY: 725736

African (AFR) AF: 0.547 AC: 18230 AN: 33330

American (AMR) AF: 0.579 AC: 25798 AN: 44554

Ashkenazi Jewish (ASJ) AF: 0.509 AC: 13228 AN: 26002

East Asian (EAS) AF: 0.397 AC: 15686 AN: 39496

South Asian (SAS) AF: 0.552 AC: 47559 AN: 86198

European-Finnish (FIN) AF: 0.606 AC: 32243 AN: 53180

Middle Eastern (MID) AF: 0.597 AC: 3413 AN: 5720

European-Non Finnish (NFE) AF: 0.621 AC: 688839 AN: 1109996

Other (OTH) AF: 0.579 AC: 34873 AN: 60180

GnomAD4 genome AF: 0.578 AC: 87681 AN: 151712 Hom.: 25616 Cov.: 32 AF XY: 0.574 AC XY: 42509 AN XY: 74120

African (AFR) AF: 0.540 AC: 22350 AN: 41388

American (AMR) AF: 0.567 AC: 8632 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.508 AC: 1761 AN: 3466

East Asian (EAS) AF: 0.347 AC: 1782 AN: 5136

South Asian (SAS) AF: 0.544 AC: 2615 AN: 4808

European-Finnish (FIN) AF: 0.598 AC: 6306 AN: 10540

Middle Eastern (MID) AF: 0.610 AC: 178 AN: 292

European-Non Finnish (NFE) AF: 0.623 AC: 42279 AN: 67836

Other (OTH) AF: 0.569 AC: 1200 AN: 2108

Alfa AF: 0.589 Hom.: 13821

Bravo AF: 0.574

Asia WGS AF: 0.490 AC: 1702 AN: 3470

EpiCase AF: 0.612

EpiControl AF: 0.610

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Leu367Leu in exon 5 of EDNRB: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 43.5% (1916/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs5351). -

May 09, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hirschsprung disease, susceptibility to, 2 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	5.2
DANN	Benign	0.78
PhyloP100		-0.12
Mutation Taster		=100/0	polymorphism (auto)

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: rs5351; hg19: chr13-78475313; COSMIC: COSV57521964;