rs139317762

Variant names:

• chr13-77898290-G-C
• rs139317762
• NM_001122659.3:c.1239C>G

Your query was ambiguous. Multiple possible variants found:

• chr13-77898290-G-C
• chr13-77898290-G-A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_001122659.3(EDNRB):​c.1239C>G​(p.Ser413Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00189 in 1,612,108 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (8 hom.)
• Consequence: EDNRB NM_001122659.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 2.36
• 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-AS1 (HGNC:49045): (EDNRB antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 13-77898290-G-C is Benign according to our data. Variant chr13-77898290-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 255140.
• BP7: Synonymous conserved (PhyloP=2.36 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00176 (268/152010) while in subpopulation NFE AF = 0.00256 (174/67896). AF 95% confidence interval is 0.00225. There are 1 homozygotes in GnomAd4. There are 120 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 8 Unknown,SD,AR,AD 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.1239C>G	p.Ser413Ser	synonymous	Exon 7 of 7	NP_001116131.1	P24530-1
	EDNRB	NM_001201397.2		c.1509C>G	p.Ser503Ser	synonymous	Exon 8 of 8	NP_001188326.1	P24530-3
	EDNRB	NM_000115.5		c.1239C>G	p.Ser413Ser	synonymous	Exon 8 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.1239C>G	p.Ser413Ser	synonymous	Exon 7 of 7	ENSP00000493527.1	P24530-1
	EDNRB	ENST00000377211.8	TSL:1	c.1509C>G	p.Ser503Ser	synonymous	Exon 8 of 8	ENSP00000366416.4	P24530-3
	EDNRB	ENST00000626030.1	TSL:1	c.1194+1569C>G		intron	N/A	ENSP00000486202.1	P24530-2

Frequencies

GnomAD3 genomes AF: 0.00176 AC: 268 AN: 151892 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00178

Gnomad ASJ AF: 0.00779

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00256

Gnomad OTH AF: 0.000959

GnomAD2 exomes AF: 0.00203 AC: 507 AN: 249344 AF XY: 0.00211

Gnomad AFR exome AF: 0.000493

Gnomad AMR exome AF: 0.00186

Gnomad ASJ exome AF: 0.00726

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00268

Gnomad OTH exome AF: 0.00477

GnomAD4 exome AF: 0.00190 AC: 2779 AN: 1460098 Hom.: 8 Cov.: 31 AF XY: 0.00196 AC XY: 1422 AN XY: 726350

African (AFR) AF: 0.000539 AC: 18 AN: 33378

American (AMR) AF: 0.00184 AC: 82 AN: 44566

Ashkenazi Jewish (ASJ) AF: 0.00737 AC: 192 AN: 26050

East Asian (EAS) AF: 0.00 AC: 0 AN: 39630

South Asian (SAS) AF: 0.00101 AC: 87 AN: 86216

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53328

Middle Eastern (MID) AF: 0.00957 AC: 55 AN: 5750

European-Non Finnish (NFE) AF: 0.00195 AC: 2170 AN: 1110920

Other (OTH) AF: 0.00279 AC: 168 AN: 60260

GnomAD4 genome AF: 0.00176 AC: 268 AN: 152010 Hom.: 1 Cov.: 33 AF XY: 0.00162 AC XY: 120 AN XY: 74292

African (AFR) AF: 0.000722 AC: 30 AN: 41530

American (AMR) AF: 0.00177 AC: 27 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.00779 AC: 27 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4820

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10606

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

European-Non Finnish (NFE) AF: 0.00256 AC: 174 AN: 67896

Other (OTH) AF: 0.000949 AC: 2 AN: 2108

Alfa AF: 0.00212 Hom.: 0

Bravo AF: 0.00198

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00338

EpiControl AF: 0.00374

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	1	-	Hirschsprung disease, susceptibility to, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	7.9
DANN	Benign	0.74
PhyloP100		2.4
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: rs139317762; hg19: chr13-78472425;