13-77901095-C-T
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2
The NM_001122659.3(EDNRB):c.914G>A(p.Ser305Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0122 in 1,611,268 control chromosomes in the GnomAD database, including 140 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001122659.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -11 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0107 AC: 1617AN: 151810Hom.: 18 Cov.: 32
GnomAD3 exomes AF: 0.0100 AC: 2516AN: 250600Hom.: 16 AF XY: 0.0101 AC XY: 1372AN XY: 135478
GnomAD4 exome AF: 0.0123 AC: 18019AN: 1459340Hom.: 122 Cov.: 30 AF XY: 0.0120 AC XY: 8743AN XY: 726064
GnomAD4 genome AF: 0.0106 AC: 1617AN: 151928Hom.: 18 Cov.: 32 AF XY: 0.0111 AC XY: 827AN XY: 74244
ClinVar
Submissions by phenotype
not provided Benign:4
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EDNRB: BS1, BS2 -
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This variant is associated with the following publications: (PMID: 22995991, 26764160, 27535533, 10874640, 8852659, 21507037) -
not specified Benign:3
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p.Ser395Asn in exon 5 of EDNRB: This variant is not expected to have clinical si gnificance because it has been identified in 1.4% (119/8600) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs5352). -
Hirschsprung disease, susceptibility to, 2 Uncertain:1Other:1
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This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Mitochondrial DNA depletion syndrome 12A (cardiomyopathic type), autosomal dominant Benign:1
The heterozygous p.Ser305Asn variant, sometimes called p.Ser205Asn or p.Ser295Asn, in EDNRB has been identified in at least 6 individuals with Hirschsprung disease, including 4 relatives from 1 family (PMID: 8852659, 10874640, 22995991). However, this variant does not segregate with disease (PMID: 10874640), and has been identified in >2% of European (Finnish) chromosomes and 5 homozygotes in ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for Hirschsprung disease. -
Waardenburg syndrome type 2A Benign:1
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Waardenburg syndrome type 4A Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at