13-77908928-C-G

Variant names:

• chr13-77908928-C-G
• rs4885493
• NM_001122659.3:c.484-5321G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001122659.3(EDNRB):​c.484-5321G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.344 in 151,872 control chromosomes in the GnomAD database, including 9,835 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.34 (9835 hom., cov: 33)
• Consequence: EDNRB NM_001122659.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.342
• Publications: 9 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: AR, AD, SD Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: PanelApp Australia, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.612 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDNRB	NM_001122659.3	MANE Select	c.484-5321G>C		intron	N/A	NP_001116131.1
	EDNRB	NM_001201397.2		c.754-5321G>C		intron	N/A	NP_001188326.1
	EDNRB	NM_000115.5		c.484-5321G>C		intron	N/A	NP_000106.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDNRB	ENST00000646607.2	MANE Select	c.484-5321G>C		intron	N/A	ENSP00000493527.1
	EDNRB	ENST00000377211.8	TSL:1	c.754-5321G>C		intron	N/A	ENSP00000366416.4
	EDNRB	ENST00000626030.1	TSL:1	c.484-5321G>C		intron	N/A	ENSP00000486202.1

Frequencies

GnomAD3 genomes AF: 0.344 AC: 52251 AN: 151752 Hom.: 9822 Cov.: 33

Gnomad AFR AF: 0.457

Gnomad AMI AF: 0.192

Gnomad AMR AF: 0.350

Gnomad ASJ AF: 0.343

Gnomad EAS AF: 0.629

Gnomad SAS AF: 0.400

Gnomad FIN AF: 0.284

Gnomad MID AF: 0.296

Gnomad NFE AF: 0.261

Gnomad OTH AF: 0.340

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.344 AC: 52304 AN: 151872 Hom.: 9835 Cov.: 33 AF XY: 0.349 AC XY: 25884 AN XY: 74220

African (AFR) AF: 0.457 AC: 18956 AN: 41456

American (AMR) AF: 0.350 AC: 5328 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.343 AC: 1188 AN: 3466

East Asian (EAS) AF: 0.630 AC: 3238 AN: 5142

South Asian (SAS) AF: 0.400 AC: 1925 AN: 4810

European-Finnish (FIN) AF: 0.284 AC: 3005 AN: 10580

Middle Eastern (MID) AF: 0.308 AC: 90 AN: 292

European-Non Finnish (NFE) AF: 0.261 AC: 17691 AN: 67864

Other (OTH) AF: 0.336 AC: 708 AN: 2108

Alfa AF: 0.299 Hom.: 919

Bravo AF: 0.355

Asia WGS AF: 0.442 AC: 1536 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.2
DANN	Benign	0.74
PhyloP100		-0.34
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: rs4885493; hg19: chr13-78483063;