chr6-12295984-G-A
Variant summary
Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong
The NM_001955.5(EDN1):c.556G>A(p.Val186Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000734 in 1,614,002 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Consequence
NM_001955.5 missense
Scores
Clinical Significance
Conservation
Publications
- question mark ears, isolatedInheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
- auriculocondylar syndrome 3Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
- auriculocondylar syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Likely_benign. The variant received -4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000480 AC: 73AN: 152096Hom.: 1 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.000453 AC: 114AN: 251468 AF XY: 0.000434 show subpopulations
GnomAD4 exome AF: 0.000760 AC: 1111AN: 1461788Hom.: 1 Cov.: 30 AF XY: 0.000710 AC XY: 516AN XY: 727208 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.000480 AC: 73AN: 152214Hom.: 1 Cov.: 32 AF XY: 0.000430 AC XY: 32AN XY: 74420 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Uncertain:1
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with EDN1-related conditions. This variant is present in population databases (rs6413478, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 186 of the EDN1 protein (p.Val186Ile). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at