NM_001122659.3:c.49C>T

Variant names:

• chr13-77918525-G-A
• rs5346
• NM_001122659.3:c.49C>T

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.49C>T​(p.Leu17Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000813 in 1,591,272 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0046 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (3 hom.)
• Consequence: EDNRB NM_001122659.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.719
• Publications: 7 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=0.004520476).
• BP6: Variant 13-77918525-G-A is Benign according to our data. Variant chr13-77918525-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 226623.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00455 (693/152226) while in subpopulation AFR AF = 0.0159 (662/41546). AF 95% confidence interval is 0.0149. There are 5 homozygotes in GnomAd4. There are 338 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDNRB	NM_001122659.3	MANE Select	c.49C>T	p.Leu17Phe	missense	Exon 1 of 7	NP_001116131.1	P24530-1
	EDNRB	NM_001201397.2		c.319C>T	p.Leu107Phe	missense	Exon 2 of 8	NP_001188326.1	P24530-3
	EDNRB	NM_000115.5		c.49C>T	p.Leu17Phe	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.49C>T	p.Leu17Phe	missense	Exon 1 of 7	ENSP00000493527.1	P24530-1
	EDNRB	ENST00000377211.8	TSL:1	c.319C>T	p.Leu107Phe	missense	Exon 2 of 8	ENSP00000366416.4	P24530-3
	EDNRB	ENST00000626030.1	TSL:1	c.49C>T	p.Leu17Phe	missense	Exon 1 of 7	ENSP00000486202.1	P24530-2

Frequencies

GnomAD3 genomes AF: 0.00454 AC: 690 AN: 152108 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00125 AC: 284 AN: 228090 AF XY: 0.000901

Gnomad AFR exome AF: 0.0173

Gnomad AMR exome AF: 0.000264

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000285

Gnomad OTH exome AF: 0.000185

GnomAD4 exome AF: 0.000417 AC: 600 AN: 1439046 Hom.: 3 Cov.: 31 AF XY: 0.000361 AC XY: 258 AN XY: 714896

African (AFR) AF: 0.0162 AC: 524 AN: 32426

American (AMR) AF: 0.000450 AC: 18 AN: 39976

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24310

East Asian (EAS) AF: 0.00 AC: 0 AN: 39632

South Asian (SAS) AF: 0.0000367 AC: 3 AN: 81774

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52370

Middle Eastern (MID) AF: 0.000532 AC: 3 AN: 5640

European-Non Finnish (NFE) AF: 0.00000453 AC: 5 AN: 1103622

Other (OTH) AF: 0.000793 AC: 47 AN: 59296

GnomAD4 genome AF: 0.00455 AC: 693 AN: 152226 Hom.: 5 Cov.: 32 AF XY: 0.00454 AC XY: 338 AN XY: 74444

African (AFR) AF: 0.0159 AC: 662 AN: 41546

American (AMR) AF: 0.00131 AC: 20 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68006

Other (OTH) AF: 0.00379 AC: 8 AN: 2110

Alfa AF: 0.00185 Hom.: 9

Bravo AF: 0.00497

ESP6500AA AF: 0.0172 AC: 76

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00146 AC: 177

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.72
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.94	N
REVEL	Benign	0.082
Sift	Uncertain	0.021	D
Sift4G	Benign	0.10	T
Polyphen		0.0040	B
Vest4		0.056
MVP		0.89
MPC		0.50
ClinPred		0.0059	T
GERP RS		1.6
PromoterAI		0.041	Neutral
Varity_R		0.068
gMVP		0.27
Mutation Taster		=94/6	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: rs5346; hg19: chr13-78492660;