rs752924362
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_023036.6(DNAI2):c.1304G>A(p.Trp435*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000663 in 1,614,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_023036.6 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152160Hom.: 0 Cov.: 30
GnomAD3 exomes AF: 0.000159 AC: 40AN: 251390Hom.: 0 AF XY: 0.000184 AC XY: 25AN XY: 135884
GnomAD4 exome AF: 0.0000657 AC: 96AN: 1461888Hom.: 0 Cov.: 31 AF XY: 0.0000633 AC XY: 46AN XY: 727244
GnomAD4 genome AF: 0.0000723 AC: 11AN: 152160Hom.: 0 Cov.: 30 AF XY: 0.0000673 AC XY: 5AN XY: 74326
ClinVar
Submissions by phenotype
Primary ciliary dyskinesia 9 Pathogenic:5
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The DNAI2 c.1304G>A (p.Trp435Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Trp435Ter variant has been reported in one study and found in three individuals with primary ciliary dyskinesia, all in a homozygous state (Knowles et al. 2013). Control data are unavailable for this variant, which is reported at a frequency of 0.003376 in the Ashkenazi Jewish population of the Genome Aggregation Database. It is suggested that this variant may be a founder variant in the Ashkenazi Jewish population (Knowles et al. 2013; Fedick et al. 2015). Based on the potential impact of stop-gained variants and the clinical evidence, the p.Trp435Ter variant is classified as likely pathogenic for primary ciliary dyskinesia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
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Primary ciliary dyskinesia Pathogenic:4
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The p.Trp435X variant in DNAI2 has been reported in 3 Ashkenazi Jewish individua ls with PCD, all of whom were homozygous for the variant, and in 2 Caucasian sib lings with PCD, both of whom were compound heterozygous with a second pathogenic DNAI2 variant (Knowles 2013, Zariwala 2013). This variant has been identified i n 14/66582 European chromosomes by the Exome Aggregation Consortium (ExAC, http: //exac.broadinstitute.org; dbSNP rs752924362). Please note that presence in the general population does not contradict pathogenicity, especially for recessive d isorders and disorders with reduced penetrance. This nonsense variant leads to a premature termination codon at position 435, which is predicted to lead to a tr uncated or absent protein. In summary, this variant meets our criteria to be cla ssified as pathogenic for PCD in an autosomal recessive manner (http://www.partn ers.org/personalizedmedicine/LMM) based on multiple reports of this variant in i ndividuals with PCD and the predicted impact of the variant. -
This sequence change creates a premature translational stop signal (p.Trp435*) in the DNAI2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DNAI2 are known to be pathogenic (PMID: 18950741, 23891469). This variant is present in population databases (rs752924362, gnomAD 0.3%). This premature translational stop signal has been observed in individuals with primary ciliary dyskinesia (PMID: 23261302, 23891469). ClinVar contains an entry for this variant (Variation ID: 228335). For these reasons, this variant has been classified as Pathogenic. -
The p.W435* pathogenic mutation (also known as c.1304G>A), located in coding exon 9 of the DNAI2 gene, results from a G to A substitution at nucleotide position 1304. This changes the amino acid from a tryptophan to a stop codon within coding exon 9. This variant was identified in several individuals in the homozygous and compound heterozygous state with a clinical diagnosis or high clinical suspicion of primary ciliary dyskinesia (Zariwala MA et al. Am J Hum Genet, 2013 Aug;93:336-45; Knowles MR et al. Am J Hum Genet, 2013 Jan;92:99-106; Shoemark A et al. Eur Respir J, 2022 Nov;60:). It was also identified in the homozygous state in an individual with bronchiectasis (Gileles-Hillel A et al. ERJ Open Res, 2020 Oct;6:). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
not provided Pathogenic:1
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25802884, 23261302, 33447612, 35753512, 23891469, 31980526, 35728977) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at