13-77898290-G-C

Position:

chr13-77898290-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BS1BS2

The NM_001122659.3(EDNRB):c.1239C>G(p.Ser413Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00189 in 1,612,108 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0018 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0019 ( 8 hom. )

Consequence

EDNRB
NM_001122659.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 2.36

Variant links:

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 links:

EDNRB-AS1 (HGNC:):

EDNRB-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 13-77898290-G-C is Benign according to our data. Variant chr13-77898290-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 255140.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=2}. Variant chr13-77898290-G-C is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=2.36 with no splicing effect.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0019 (2779/1460098) while in subpopulation MID AF= 0.00957 (55/5750). AF 95% confidence interval is 0.00755. There are 8 homozygotes in gnomad4_exome. There are 1422 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 8 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDNRB	NM_001122659.3 linkuse as main transcript	c.1239C>G	p.Ser413Ser	synonymous_variant	7/7	ENST00000646607.2	NP_001116131.1	P24530-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EDNRB	ENST00000646607.2 linkuse as main transcript	c.1239C>G	p.Ser413Ser	synonymous_variant	7/7		NM_001122659.3	ENSP00000493527.1		P24530-1

Frequencies

GnomAD3 genomes

AF:

0.00176

AC:

268

AN:

151892

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00178

Gnomad ASJ

AF:

0.00779

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00256

Gnomad OTH

AF:

0.000959

GnomAD3 exomes

AF:

0.00203

AC:

507

AN:

249344

Hom.:

AF XY:

0.00211

AC XY:

285

AN XY:

134874

show subpopulations

Gnomad AFR exome

AF:

0.000493

Gnomad AMR exome

AF:

0.00186

Gnomad ASJ exome

AF:

0.00726

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00105

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.00268

Gnomad OTH exome

AF:

0.00477

GnomAD4 exome

AF:

0.00190

AC:

2779

AN:

1460098

Hom.:

Cov.:

AF XY:

0.00196

AC XY:

1422

AN XY:

726350

show subpopulations

Gnomad4 AFR exome

AF:

0.000539

Gnomad4 AMR exome

AF:

0.00184

Gnomad4 ASJ exome

AF:

0.00737

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00101

Gnomad4 FIN exome

AF:

0.000131

Gnomad4 NFE exome

AF:

0.00195

Gnomad4 OTH exome

AF:

0.00279

GnomAD4 genome

AF:

0.00176

AC:

268

AN:

152010

Hom.:

Cov.:

AF XY:

0.00162

AC XY:

120

AN XY:

74292

show subpopulations

Gnomad4 AFR

AF:

0.000722

Gnomad4 AMR

AF:

0.00177

Gnomad4 ASJ

AF:

0.00779

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.00256

Gnomad4 OTH

AF:

0.000949

Alfa

AF:

0.00212

Hom.:

Bravo

AF:

0.00198

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00338

EpiControl

AF:

0.00374

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	EDNRB: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 16, 2021	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Ser503Ser in exon 8 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 0.3% (27/8600) of Eu ropean American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS). -

Hirschsprung disease, susceptibility to, 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

7.9

DANN

Benign

0.74

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over