13-77903539-A-G

Variant names:

• chr13-77903539-A-G
• rs5348
• NM_001122659.3:c.552T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001122659.3(EDNRB):​c.552T>C​(p.Ser184Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.997 in 1,612,874 control chromosomes in the GnomAD database, including 801,580 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S184S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.99 (73855 hom., cov: 31)
  • Exomes 𝑓: 1.0 (727725 hom.)
• Consequence: EDNRB NM_001122659.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.81
• 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-AS1 (HGNC:49045): (EDNRB antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 13-77903539-A-G is Benign according to our data. Variant chr13-77903539-A-G is described in ClinVar as Benign. ClinVar VariationId is 226625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.81 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 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.552T>C	p.Ser184Ser	synonymous	Exon 2 of 7	NP_001116131.1
	EDNRB	NM_001201397.2		c.822T>C	p.Ser274Ser	synonymous	Exon 3 of 8	NP_001188326.1
	EDNRB	NM_000115.5		c.552T>C	p.Ser184Ser	synonymous	Exon 3 of 8	NP_000106.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDNRB	ENST00000646607.2	MANE Select	c.552T>C	p.Ser184Ser	synonymous	Exon 2 of 7	ENSP00000493527.1
	EDNRB	ENST00000377211.8	TSL:1	c.822T>C	p.Ser274Ser	synonymous	Exon 3 of 8	ENSP00000366416.4
	EDNRB	ENST00000626030.1	TSL:1	c.552T>C	p.Ser184Ser	synonymous	Exon 2 of 7	ENSP00000486202.1

Frequencies

GnomAD3 genomes AF: 0.985 AC: 149684 AN: 151896 Hom.: 73796 Cov.: 31

Gnomad AFR AF: 0.951

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.992

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.994

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.997

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.989

GnomAD2 exomes AF: 0.996 AC: 249287 AN: 250374 AF XY: 0.996

Gnomad AFR exome AF: 0.951

Gnomad AMR exome AF: 0.997

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.997

GnomAD4 exome AF: 0.998 AC: 1458106 AN: 1460860 Hom.: 727725 Cov.: 65 AF XY: 0.998 AC XY: 725418 AN XY: 726756

African (AFR) AF: 0.950 AC: 31736 AN: 33402

American (AMR) AF: 0.997 AC: 44448 AN: 44598

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26073 AN: 26074

East Asian (EAS) AF: 1.00 AC: 39678 AN: 39682

South Asian (SAS) AF: 0.994 AC: 85759 AN: 86240

European-Finnish (FIN) AF: 1.00 AC: 53406 AN: 53406

Middle Eastern (MID) AF: 0.996 AC: 5732 AN: 5754

European-Non Finnish (NFE) AF: 1.00 AC: 1111198 AN: 1111380

Other (OTH) AF: 0.996 AC: 60076 AN: 60324

GnomAD4 genome AF: 0.985 AC: 149802 AN: 152014 Hom.: 73855 Cov.: 31 AF XY: 0.986 AC XY: 73250 AN XY: 74308

African (AFR) AF: 0.951 AC: 39484 AN: 41500

American (AMR) AF: 0.992 AC: 15126 AN: 15248

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3468 AN: 3468

East Asian (EAS) AF: 1.00 AC: 5128 AN: 5128

South Asian (SAS) AF: 0.994 AC: 4792 AN: 4820

European-Finnish (FIN) AF: 1.00 AC: 10622 AN: 10622

Middle Eastern (MID) AF: 0.997 AC: 293 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 67885 AN: 67908

Other (OTH) AF: 0.990 AC: 2092 AN: 2114

Alfa AF: 0.994 Hom.: 48752

Bravo AF: 0.984

Asia WGS AF: 0.997 AC: 3468 AN: 3478

EpiCase AF: 1.00

EpiControl AF: 1.00

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	ABCD syndrome (1)
-	-	1	ABCD syndrome;C1838564:Hirschsprung disease, susceptibility to, 2;C1848519:Waardenburg syndrome type 4A (1)
-	-	1	not specified (1)
-	-	1	Waardenburg syndrome type 4A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.0
DANN	Benign	0.63
PhyloP100		-1.8
PromoterAI		-0.0036	Neutral
Mutation Taster		=99/1	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: rs5348; hg19: chr13-78477674; COSMIC: COSV108162878;