NM_001122659.3:c.484-6389A>G

Variant names:

• chr13-77909996-T-C
• rs7982910
• NM_001122659.3:c.484-6389A>G

Variant summary

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

The NM_001122659.3(EDNRB):​c.484-6389A>G variant causes a intron change. The variant allele was found at a frequency of 0.35 in 151,740 control chromosomes in the GnomAD database, including 11,241 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 0.35 (11241 hom., cov: 31)
• Consequence: EDNRB NM_001122659.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.64
• Publications: 3 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=-0.79).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.485 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDNRB	NM_001122659.3	c.484-6389A>G		intron_variant	Intron 1 of 6	ENST00000646607.2	NP_001116131.1
EDNRB	NM_001201397.2	c.754-6389A>G		intron_variant	Intron 2 of 7		NP_001188326.1
EDNRB	NM_000115.5	c.484-6389A>G		intron_variant	Intron 2 of 7		NP_000106.1
EDNRB	NM_003991.4	c.484-6389A>G		intron_variant	Intron 1 of 6		NP_003982.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDNRB	ENST00000646607.2	c.484-6389A>G		intron_variant	Intron 1 of 6		NM_001122659.3	ENSP00000493527.1

Frequencies

GnomAD3 genomes AF: 0.350 AC: 53039 AN: 151622 Hom.: 11242 Cov.: 31

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.455

Gnomad AMR AF: 0.400

Gnomad ASJ AF: 0.346

Gnomad EAS AF: 0.193

Gnomad SAS AF: 0.347

Gnomad FIN AF: 0.380

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.489

Gnomad OTH AF: 0.370

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

GnomAD4 genome AF: 0.350 AC: 53035 AN: 151740 Hom.: 11241 Cov.: 31 AF XY: 0.342 AC XY: 25369 AN XY: 74168

African (AFR) AF: 0.111 AC: 4616 AN: 41438

American (AMR) AF: 0.401 AC: 6102 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.346 AC: 1197 AN: 3462

East Asian (EAS) AF: 0.192 AC: 988 AN: 5136

South Asian (SAS) AF: 0.346 AC: 1661 AN: 4798

European-Finnish (FIN) AF: 0.380 AC: 4008 AN: 10546

Middle Eastern (MID) AF: 0.384 AC: 113 AN: 294

European-Non Finnish (NFE) AF: 0.489 AC: 33161 AN: 67818

Other (OTH) AF: 0.368 AC: 774 AN: 2104

Alfa AF: 0.417 Hom.: 4215

Bravo AF: 0.341

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	14
DANN	Benign	0.76
PhyloP100		3.6
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: rs7982910; hg19: chr13-78484131;