dbSNP rs5350: EDNRB:p.Thr244Met (chr13-77903226-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001122659.3(EDNRB):c.731C>T(p.Thr244Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000633 in 1,612,874 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T244T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0032 ( 7 hom., cov: 32)

Exomes 𝑓: 0.00037 ( 3 hom. )

Consequence

EDNRB
NM_001122659.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.78

Publications

10 publications found

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:49045): (EDNRB antisense RNA 1)

EDNRB-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008720815).

BP6

Variant 13-77903226-G-A is Benign according to our data. Variant chr13-77903226-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 255141.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00319 (484/151882) while in subpopulation AFR AF = 0.0108 (448/41456). AF 95% confidence interval is 0.00998. There are 7 homozygotes in GnomAd4. There are 223 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AD,AR,Unknown,SD gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EDNRB	NM_001122659.3	MANE Select	c.731C>T	p.Thr244Met	missense	Exon 3 of 7	NP_001116131.1	P24530-1
EDNRB	NM_001201397.2		c.1001C>T	p.Thr334Met	missense	Exon 4 of 8	NP_001188326.1	P24530-3
EDNRB	NM_000115.5		c.731C>T	p.Thr244Met	missense	Exon 4 of 8	NP_000106.1	P24530-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EDNRB	ENST00000646607.2	MANE Select	c.731C>T	p.Thr244Met	missense	Exon 3 of 7	ENSP00000493527.1	P24530-1
EDNRB	ENST00000377211.8	TSL:1	c.1001C>T	p.Thr334Met	missense	Exon 4 of 8	ENSP00000366416.4	P24530-3
EDNRB	ENST00000626030.1	TSL:1	c.731C>T	p.Thr244Met	missense	Exon 3 of 7	ENSP00000486202.1	P24530-2

Frequencies

GnomAD3 genomes

AF:

0.00318

AC:

482

AN:

151764

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0108

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00158

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.000416

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000589

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.000801

AC:

201

AN:

250922

AF XY:

0.000546

show subpopulations

Gnomad AFR exome

AF:

0.0107

Gnomad AMR exome

AF:

0.000522

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000368

AC:

537

AN:

1460992

Hom.:

Cov.:

AF XY:

0.000325

AC XY:

236

AN XY:

726816

show subpopulations

African (AFR)

AF:

0.0113

AC:

376

AN:

33408

American (AMR)

AF:

0.000627

AC:

AN:

44634

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26092

East Asian (EAS)

AF:

0.000126

AC:

AN:

39676

South Asian (SAS)

AF:

0.000104

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.000868

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000405

AC:

AN:

1111462

Other (OTH)

AF:

0.00113

AC:

AN:

60324

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

113

150

188

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00319

AC:

484

AN:

151882

Hom.:

Cov.:

AF XY:

0.00300

AC XY:

223

AN XY:

74238

show subpopulations

African (AFR)

AF:

0.0108

AC:

448

AN:

41456

American (AMR)

AF:

0.00157

AC:

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000195

AC:

AN:

5136

South Asian (SAS)

AF:

0.000417

AC:

AN:

4800

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000589

AC:

AN:

67870

Other (OTH)

AF:

0.00236

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

105

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00116

Hom.:

Bravo

AF:

0.00346

ESP6500AA

AF:

0.0125

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00105

AC:

127

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Hirschsprung disease, susceptibility to, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.73

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.79

MetaRNN

Benign

0.0087

MetaSVM

Benign

-0.37

MutationAssessor

Uncertain

2.4

PhyloP100

1.8

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.24

Sift

Benign

0.058

Sift4G

Uncertain

0.026

Polyphen

1.0

Vest4

0.19

MVP

0.92

MPC

1.2

ClinPred

0.034

GERP RS

3.0

PromoterAI

-0.029

Neutral

(source)

Varity_R

0.076

gMVP

0.79

Mutation Taster

=89/11

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over