rs727504972
Variant summary
Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3
The NM_017950.4(CCDC40):c.940-7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000886 in 1,613,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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_017950.4 splice_region, intron
Scores
Clinical Significance
Conservation
Publications
- primary ciliary dyskinesia 15Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, Laboratory for Molecular Medicine
- primary ciliary dyskinesiaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- autoimmune diseaseInheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
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ACMG classification
Our verdict: Uncertain_significance. The variant received 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CCDC40 | NM_017950.4 | c.940-7G>A | splice_region_variant, intron_variant | Intron 6 of 19 | ENST00000397545.9 | NP_060420.2 | ||
CCDC40 | NM_001243342.2 | c.940-7G>A | splice_region_variant, intron_variant | Intron 6 of 17 | NP_001230271.1 | |||
CCDC40 | NM_001330508.2 | c.940-7G>A | splice_region_variant, intron_variant | Intron 6 of 10 | NP_001317437.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000461 AC: 7AN: 151944Hom.: 0 Cov.: 31 show subpopulations
GnomAD2 exomes AF: 0.0000441 AC: 11AN: 249430 AF XY: 0.0000443 show subpopulations
GnomAD4 exome AF: 0.0000930 AC: 136AN: 1461798Hom.: 0 Cov.: 33 AF XY: 0.0000963 AC XY: 70AN XY: 727202 show subpopulations
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152062Hom.: 0 Cov.: 31 AF XY: 0.0000538 AC XY: 4AN XY: 74318 show subpopulations
ClinVar
Submissions by phenotype
not provided Uncertain:2
In silico analysis supports a deleterious effect on splicing; Has not been previously published as pathogenic or benign to our knowledge -
The CCDC40 c.940-7G>A variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs727504972), ClinVar (classified as a VUS by Laboratory for Molecular Medicine and Illumina) and LOVD 3.0 (classified as a VUS). The variant was identified in control databases in 12 of 280788 chromosomes at a frequency of 0.000043 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 11 of 128576 chromosomes (freq: 0.000086) and European (Finnish) in 1 of 25020 chromosomes (freq: 0.00004), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, Other or South Asian populations. The c.940-7G>A variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, four of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing and the creation of a novel 3' splice site. However this splicing prediction has not been confirmed by RNA analysis. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Primary ciliary dyskinesia 15 Uncertain:2
The CCDC40 c.940-7G>A variant (rs727504972), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 179591). This variant is found in the non-Finnish European population with an allele frequency of 0.009% (11/128,576 alleles) in the Genome Aggregation Database (v2.1.1). This is an intronic variant and computational analyses (Alamut Visual Plus v.1.5.1) predict that this variant may impact splicing by creating a novel cryptic acceptor splice site and weakening the nearby canonical acceptor splice site. However, given the lack of clinical and functional data, the significance of this variant is uncertain at this time. -
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. -
not specified Uncertain:1
The c.940-7G>A variant in CCDC40 has not been previously reported in individuals with pulmonary disease. Data from large population studies is insufficient to a ssess the frequency of this variant. This variant is located in the 3' splice re gion. Computational tools strongly suggest an impact to splicing; however, this information is not predictive enough to determine pathogenicity. In summary, add itional studies are needed to fully assess its clinical significance. -
Primary ciliary dyskinesia Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at