rs753716586
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_017950.4(CCDC40):c.3180+6C>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0001 in 1,613,700 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00011 ( 1 hom. )
Consequence
CCDC40
NM_017950.4 splice_donor_region, intron
NM_017950.4 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.00004409
2
Clinical Significance
Conservation
PhyloP100: -0.0130
Genes affected
CCDC40 (HGNC:26090): (coiled-coil domain 40 molecular ruler complex subunit) This gene encodes a protein that is necessary for motile cilia function. It functions in correct left-right axis formation by regulating the assembly of the inner dynein arm and the dynein regulatory complexes, which control ciliary beat. Mutations in this gene cause ciliary dyskinesia type 15, a disorder due to defects in cilia motility. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2011]
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ACMG classification
Classification made for transcript
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=-0.89).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CCDC40 | NM_017950.4 | c.3180+6C>G | splice_donor_region_variant, intron_variant | ENST00000397545.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CCDC40 | ENST00000397545.9 | c.3180+6C>G | splice_donor_region_variant, intron_variant | 5 | NM_017950.4 | P2 | |||
CCDC40 | ENST00000574799.5 | n.2717+6C>G | splice_donor_region_variant, intron_variant, non_coding_transcript_variant | 1 | |||||
CCDC40 | ENST00000572253.5 | n.3437C>G | non_coding_transcript_exon_variant | 6/6 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152178Hom.: 0 Cov.: 33
GnomAD3 genomes
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GnomAD3 exomes AF: 0.0000603 AC: 15AN: 248938Hom.: 0 AF XY: 0.0000592 AC XY: 8AN XY: 135228
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GnomAD4 exome AF: 0.000107 AC: 156AN: 1461522Hom.: 1 Cov.: 35 AF XY: 0.000106 AC XY: 77AN XY: 727020
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GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152178Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74354
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 23, 2022 | This sequence change falls in intron 19 of the CCDC40 gene. It does not directly change the encoded amino acid sequence of the CCDC40 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs753716586, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CCDC40-related conditions. ClinVar contains an entry for this variant (Variation ID: 454890). 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 is not likely to affect RNA splicing. 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. - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at