rs876657804

chr13-77896568-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000626030.1(EDNRB):c.1195-10C>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000716 in 1,397,258 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: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: EDNRB ENST00000626030.1 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001460
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.948

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:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDNRB	NM_001122659.3	c.*1632C>A		3_prime_UTR_variant	7/7	ENST00000646607.2
EDNRB-AS1	NR_103853.1	n.1695-11124G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDNRB	ENST00000646607.2	c.*1632C>A		3_prime_UTR_variant	7/7		NM_001122659.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000629 AC: 1 AN: 158902 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 84256

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000414

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.16e-7 AC: 1 AN: 1397258 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 689376

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000281

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 21, 2015

The c.1195-10C>A variant in EDNRB has not been previously reported in individual s with hearing loss. Data from large population studies are insufficient to asse ss the frequency of this variant. This variant is located in the 3' splice regio n. Computational tools do not suggest an impact to splicing. However, this infor mation is not predictive enough to rule out pathogenicity. In summary, the clini cal significance of the c.1195-10C>A variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.27
Dann	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000015
dbscSNV1_RF	Benign	0.0
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

Publications

LitVar

Other links and lift over

dbSNP: rs876657804; hg19: chr13-78470703; COSMIC: COSV105890559; COSMIC: COSV105890559;