rs5351

Variant names:

• chr13-77901178-T-C
• rs5351
• NM_001122659.3:c.831A>G

Your query was ambiguous. Multiple possible variants found:

• chr13-77901178-T-C
• chr13-77901178-T-G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001122659.3(EDNRB):​c.831A>G​(p.Leu277Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.601 in 1,610,368 control chromosomes in the GnomAD database, including 293,077 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (25616 hom., cov: 32)
  • Exomes 𝑓: 0.60 (267461 hom.)
• Consequence: EDNRB NM_001122659.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.124
• Publications: 59 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-AS1 (HGNC:49045): (EDNRB antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 13-77901178-T-C is Benign according to our data. Variant chr13-77901178-T-C is described in ClinVar as Benign. ClinVar VariationId is 226622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.124 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.618 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDNRB	NM_001122659.3	MANE Select	c.831A>G	p.Leu277Leu	synonymous	Exon 4 of 7	NP_001116131.1	P24530-1
	EDNRB	NM_001201397.2		c.1101A>G	p.Leu367Leu	synonymous	Exon 5 of 8	NP_001188326.1	P24530-3
	EDNRB	NM_000115.5		c.831A>G	p.Leu277Leu	synonymous	Exon 5 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.831A>G	p.Leu277Leu	synonymous	Exon 4 of 7	ENSP00000493527.1	P24530-1
	EDNRB	ENST00000377211.8	TSL:1	c.1101A>G	p.Leu367Leu	synonymous	Exon 5 of 8	ENSP00000366416.4	P24530-3
	EDNRB	ENST00000626030.1	TSL:1	c.831A>G	p.Leu277Leu	synonymous	Exon 4 of 7	ENSP00000486202.1	P24530-2

Frequencies

GnomAD3 genomes AF: 0.578 AC: 87644 AN: 151594 Hom.: 25610 Cov.: 32

Gnomad AFR AF: 0.540

Gnomad AMI AF: 0.635

Gnomad AMR AF: 0.566

Gnomad ASJ AF: 0.508

Gnomad EAS AF: 0.348

Gnomad SAS AF: 0.544

Gnomad FIN AF: 0.598

Gnomad MID AF: 0.615

Gnomad NFE AF: 0.623

Gnomad OTH AF: 0.572

GnomAD2 exomes AF: 0.574 AC: 143733 AN: 250254 AF XY: 0.574

Gnomad AFR exome AF: 0.546

Gnomad AMR exome AF: 0.583

Gnomad ASJ exome AF: 0.511

Gnomad EAS exome AF: 0.330

Gnomad FIN exome AF: 0.599

Gnomad NFE exome AF: 0.621

Gnomad OTH exome AF: 0.583

GnomAD4 exome AF: 0.603 AC: 879869 AN: 1458656 Hom.: 267461 Cov.: 48 AF XY: 0.601 AC XY: 436238 AN XY: 725736

African (AFR) AF: 0.547 AC: 18230 AN: 33330

American (AMR) AF: 0.579 AC: 25798 AN: 44554

Ashkenazi Jewish (ASJ) AF: 0.509 AC: 13228 AN: 26002

East Asian (EAS) AF: 0.397 AC: 15686 AN: 39496

South Asian (SAS) AF: 0.552 AC: 47559 AN: 86198

European-Finnish (FIN) AF: 0.606 AC: 32243 AN: 53180

Middle Eastern (MID) AF: 0.597 AC: 3413 AN: 5720

European-Non Finnish (NFE) AF: 0.621 AC: 688839 AN: 1109996

Other (OTH) AF: 0.579 AC: 34873 AN: 60180

GnomAD4 genome AF: 0.578 AC: 87681 AN: 151712 Hom.: 25616 Cov.: 32 AF XY: 0.574 AC XY: 42509 AN XY: 74120

African (AFR) AF: 0.540 AC: 22350 AN: 41388

American (AMR) AF: 0.567 AC: 8632 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.508 AC: 1761 AN: 3466

East Asian (EAS) AF: 0.347 AC: 1782 AN: 5136

South Asian (SAS) AF: 0.544 AC: 2615 AN: 4808

European-Finnish (FIN) AF: 0.598 AC: 6306 AN: 10540

Middle Eastern (MID) AF: 0.610 AC: 178 AN: 292

European-Non Finnish (NFE) AF: 0.623 AC: 42279 AN: 67836

Other (OTH) AF: 0.569 AC: 1200 AN: 2108

Alfa AF: 0.589 Hom.: 13821

Bravo AF: 0.574

Asia WGS AF: 0.490 AC: 1702 AN: 3470

EpiCase AF: 0.612

EpiControl AF: 0.610

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	5.2
DANN	Benign	0.78
PhyloP100		-0.12
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: rs5351; hg19: chr13-78475313; COSMIC: COSV57521964;