rs1801710

Variant names:

• chr13-77918405-C-T
• rs1801710
• NM_001122659.3:c.169G>A

Your query was ambiguous. Multiple possible variants found:

• chr13-77918405-C-T
• chr13-77918405-C-G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001122659.3(EDNRB):​c.169G>A​(p.Gly57Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00634 in 1,597,292 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. G57D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0045 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0065 (44 hom.)
• Consequence: EDNRB NM_001122659.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8 O:1
• Conservation: PhyloP100: -0.0970
• Publications: 22 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 Gene-Disease associations (from GenCC):

• ABCD syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Waardenburg syndrome type 4A

  Inheritance: SD, AR, AD Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, ClinGen
• Waardenburg syndrome type 2

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Waardenburg-Shah syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Hirschsprung disease, susceptibility to, 2

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.004221499).
• BP6: Variant 13-77918405-C-T is Benign according to our data. Variant chr13-77918405-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 16637.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00452 (687/152150) while in subpopulation NFE AF = 0.0079 (537/68014). AF 95% confidence interval is 0.00734. There are 1 homozygotes in GnomAd4. There are 317 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 44 Unknown,SD,AR,AD 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDNRB	NM_001122659.3	MANE Select	c.169G>A	p.Gly57Ser	missense	Exon 1 of 7	NP_001116131.1	P24530-1
	EDNRB	NM_001201397.2		c.439G>A	p.Gly147Ser	missense	Exon 2 of 8	NP_001188326.1	P24530-3
	EDNRB	NM_000115.5		c.169G>A	p.Gly57Ser	missense	Exon 2 of 8	NP_000106.1	P24530-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDNRB	ENST00000646607.2	MANE Select	c.169G>A	p.Gly57Ser	missense	Exon 1 of 7	ENSP00000493527.1	P24530-1
	EDNRB	ENST00000377211.8	TSL:1	c.439G>A	p.Gly147Ser	missense	Exon 2 of 8	ENSP00000366416.4	P24530-3
	EDNRB	ENST00000626030.1	TSL:1	c.169G>A	p.Gly57Ser	missense	Exon 1 of 7	ENSP00000486202.1	P24530-2

Frequencies

GnomAD3 genomes AF: 0.00452 AC: 687 AN: 152032 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00643

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00789

Gnomad OTH AF: 0.00336

GnomAD2 exomes AF: 0.00513 AC: 1225 AN: 238706 AF XY: 0.00523

Gnomad AFR exome AF: 0.00143

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.000117

Gnomad EAS exome AF: 0.0000553

Gnomad FIN exome AF: 0.00649

Gnomad NFE exome AF: 0.00927

Gnomad OTH exome AF: 0.00384

GnomAD4 exome AF: 0.00654 AC: 9444 AN: 1445142 Hom.: 44 Cov.: 31 AF XY: 0.00640 AC XY: 4593 AN XY: 717122

African (AFR) AF: 0.00134 AC: 44 AN: 32794

American (AMR) AF: 0.000535 AC: 23 AN: 43026

Ashkenazi Jewish (ASJ) AF: 0.000361 AC: 9 AN: 24906

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39498

South Asian (SAS) AF: 0.000405 AC: 34 AN: 83958

European-Finnish (FIN) AF: 0.00845 AC: 446 AN: 52788

Middle Eastern (MID) AF: 0.000881 AC: 5 AN: 5676

European-Non Finnish (NFE) AF: 0.00776 AC: 8562 AN: 1102986

Other (OTH) AF: 0.00533 AC: 317 AN: 59510

GnomAD4 genome AF: 0.00452 AC: 687 AN: 152150 Hom.: 1 Cov.: 31 AF XY: 0.00426 AC XY: 317 AN XY: 74390

African (AFR) AF: 0.00135 AC: 56 AN: 41526

American (AMR) AF: 0.00111 AC: 17 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4806

European-Finnish (FIN) AF: 0.00643 AC: 68 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00790 AC: 537 AN: 68014

Other (OTH) AF: 0.00332 AC: 7 AN: 2108

Alfa AF: 0.00674 Hom.: 25

Bravo AF: 0.00383

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00856 AC: 33

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00884 AC: 76

ExAC AF: 0.00620 AC: 753

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	-	3	not specified (3)
-	-	1	Hirschsprung disease, susceptibility to, 2 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	4.7
DANN	Benign	0.96
DEOGEN2	Benign	0.28	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.097
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.028
Sift	Benign	0.076	T
Sift4G	Benign	0.23	T
Polyphen		0.27	B
Vest4		0.052
MVP		0.38
MPC		0.46
ClinPred		0.00026	T
GERP RS		-0.44
PromoterAI		0.021	Neutral
Varity_R		0.10
gMVP		0.29
Mutation Taster		=96/4	polymorphism

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: rs1801710; hg19: chr13-78492540; COSMIC: COSV100526052; COSMIC: COSV100526052;