rs769223754
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_181426.2(CCDC39):c.1874G>T(p.Ser625Ile) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000503 in 1,569,294 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_181426.2 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152100Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000695 AC: 16AN: 230198Hom.: 0 AF XY: 0.0000719 AC XY: 9AN XY: 125152
GnomAD4 exome AF: 0.0000501 AC: 71AN: 1417194Hom.: 0 Cov.: 29 AF XY: 0.0000569 AC XY: 40AN XY: 702680
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152100Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74298
ClinVar
Submissions by phenotype
Primary ciliary dyskinesia Pathogenic:2
The p.S625I variant (also known as c.1874G>T), located in coding exon 13 of the CCDC39 gene, results from a G to T substitution at nucleotide position 1874. The amino acid change results in serine to isoleucine at codon 625, an amino acid with dissimilar properties. However, this change occurs in the last base pair of coding exon 13, which makes it likely to have some effect on normal mRNA splicing. This alteration has been detected in trans with a pathogenic mutation in CCDC39 by our laboratory. Both the nucleotide and amino acid positions are highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 625 of the CCDC39 protein (p.Ser625Ile). This variant also falls at the last nucleotide of exon 13, which is part of the consensus splice site for this exon. This variant is present in population databases (rs769223754, gnomAD 0.01%). This missense change has been observed in individual(s) with primary ciliary dyskinesia (internal data). ClinVar contains an entry for this variant (Variation ID: 228475). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Primary ciliary dyskinesia 14 Pathogenic:1
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CCDC39-related disorder Pathogenic:1
The CCDC39 c.1874G>T variant is predicted to result in the amino acid substitution p.Ser625Ile. To our knowledge, this variant has not been reported in the literature. This variant occurs at the last nucleotide of exon 13 in CCDC39 and is predicted to weaken the canonical splice donor site based on available splicing prediction programs (Alamut Visual v1.6.1). This variant has been confirmed in trans with a pathogenic CCDC39 variant in one individual with clinical features of primary ciliary dyskinesia (Internal Data, PreventionGenetics). This variant is reported in 0.013% of alleles in individuals of European (non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-180359781-C-A). This variant is classified as likely pathogenic. -
not specified Uncertain:1
The p.Ser625Ile variant in CCDC39 has not been previously reported in individual s with pulmonary disease, but has been identified in 10/65788 European chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs769223754). Computational prediction tools and conservation analysis sugge st that the p.Ser625Ile variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This variant is located in the last three bases of the exon, which is part of the 5? splice region. Computa tional tools do not suggest an impact to splicing. However, this information is not predictive enough to rule out pathogenicity. In summary, the clinical signif icance of the p.Ser625Ile variant is uncertain. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at