ENST00000626030.1:c.1215T>C

Variant names:

• chr13-77896538-A-G
• rs202174312
• ENST00000626030.1:c.1215T>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP7 BS1_Supporting

The ENST00000626030.1(EDNRB):​c.1215T>C​(p.Asn405Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000303 in 1,566,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: EDNRB ENST00000626030.1 synonymous
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.642
• Publications: 2 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP7: Synonymous conserved (PhyloP=0.642 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000197 (30/152128) while in subpopulation AMR AF = 0.000393 (6/15264). AF 95% confidence interval is 0.000231. There are 0 homozygotes in GnomAd4. There are 14 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000626030.1. 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.*1662T>C		3_prime_UTR	Exon 7 of 7	NP_001116131.1
	EDNRB	NM_003991.4		c.1215T>C	p.Asn405Asn	synonymous	Exon 7 of 7	NP_003982.1
	EDNRB	NM_001201397.2		c.*1662T>C		3_prime_UTR	Exon 8 of 8	NP_001188326.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDNRB	ENST00000626030.1	TSL:1	c.1215T>C	p.Asn405Asn	synonymous	Exon 7 of 7	ENSP00000486202.1
	EDNRB	ENST00000646607.2	MANE Select	c.*1662T>C		3_prime_UTR	Exon 7 of 7	ENSP00000493527.1
	EDNRB	ENST00000377211.8	TSL:1	c.*1662T>C		3_prime_UTR	Exon 8 of 8	ENSP00000366416.4

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152010 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000394

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000164 AC: 30 AN: 183356 AF XY: 0.000205

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000109

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000117

Gnomad NFE exome AF: 0.000320

Gnomad OTH exome AF: 0.000205

GnomAD4 exome AF: 0.000315 AC: 445 AN: 1414862 Hom.: 0 Cov.: 31 AF XY: 0.000306 AC XY: 214 AN XY: 699460

African (AFR) AF: 0.0000306 AC: 1 AN: 32682

American (AMR) AF: 0.0000774 AC: 3 AN: 38768

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25388

East Asian (EAS) AF: 0.0000262 AC: 1 AN: 38236

South Asian (SAS) AF: 0.0000124 AC: 1 AN: 80816

European-Finnish (FIN) AF: 0.0000794 AC: 4 AN: 50386

Middle Eastern (MID) AF: 0.000483 AC: 2 AN: 4140

European-Non Finnish (NFE) AF: 0.000387 AC: 420 AN: 1086060

Other (OTH) AF: 0.000223 AC: 13 AN: 58386

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152128 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74362

African (AFR) AF: 0.00 AC: 0 AN: 41536

American (AMR) AF: 0.000393 AC: 6 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000339 AC: 23 AN: 67946

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000173 Hom.: 0

Bravo AF: 0.000185

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hirschsprung disease, susceptibility to, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	8.1
DANN	Benign	0.47
PhyloP100		0.64
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs202174312; hg19: chr13-78470673;