NM_001122659.3:c.550_552delTCTinsCCC

Variant names:

• chr13-77903539-AGA-GGG
• NM_001122659.3:c.550_552delTCTinsCCC
• EDNRB p.Ser184Pro

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PS1 PM1 PP3

The NM_001122659.3(EDNRB):​c.550_552delTCTinsCCC​(p.Ser184Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Synonymous variant affecting the same amino acid position (i.e. S184S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: EDNRB NM_001122659.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.60
• Publications: 0 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_pathogenic. The variant received 7 ACMG points.

• PS1: Transcript NM_001122659.3 (EDNRB) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001122659.3
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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.550_552delTCTinsCCC	p.Ser184Pro	missense	N/A	NP_001116131.1	P24530-1
	EDNRB	NM_001201397.2		c.820_822delTCTinsCCC	p.Ser274Pro	missense	N/A	NP_001188326.1	P24530-3
	EDNRB	NM_000115.5		c.550_552delTCTinsCCC	p.Ser184Pro	missense	N/A	NP_000106.1	P24530-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDNRB	ENST00000646607.2	MANE Select	c.550_552delTCTinsCCC	p.Ser184Pro	missense	N/A	ENSP00000493527.1	P24530-1
	EDNRB	ENST00000377211.8	TSL:1	c.820_822delTCTinsCCC	p.Ser274Pro	missense	N/A	ENSP00000366416.4	P24530-3
	EDNRB	ENST00000626030.1	TSL:1	c.550_552delTCTinsCCC	p.Ser184Pro	missense	N/A	ENSP00000486202.1	P24530-2

Frequencies

GnomAD3 genomes Cov.: 31

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

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.6

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr13-78477674;