GeneBe

rs878855042

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_017950.4(CCDC40):​c.2852dupT​(p.Lys952GlufsTer46) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,558 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L951L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 34)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

CCDC40
NM_017950.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 1.14
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-80095281-C-CT is Pathogenic according to our data. Variant chr17-80095281-C-CT is described in ClinVar as [Pathogenic]. Clinvar id is 241240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CCDC40NM_017950.4 linkc.2852dupT p.Lys952GlufsTer46 frameshift_variant Exon 18 of 20 ENST00000397545.9 NP_060420.2 Q4G0X9-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CCDC40ENST00000397545.9 linkc.2852dupT p.Lys952GlufsTer46 frameshift_variant Exon 18 of 20 5 NM_017950.4 ENSP00000380679.4 Q4G0X9-1
CCDC40ENST00000574799.5 linkn.2389dupT non_coding_transcript_exon_variant Exon 14 of 16 1
CCDC40ENST00000572253.5 linkn.3103dupT non_coding_transcript_exon_variant Exon 5 of 6 2
CCDC40ENST00000575431.1 linkn.496dupT non_coding_transcript_exon_variant Exon 4 of 4 3

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461558
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727092
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33474
American (AMR)
AF:
0.00
AC:
0
AN:
44720
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53116
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00000360
AC:
4
AN:
1111994
Other (OTH)
AF:
0.00
AC:
0
AN:
60392
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.513
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
34

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Primary ciliary dyskinesia Pathogenic:2
Dec 27, 2017
Ambry Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.2852dupT pathogenic mutation, located in coding exon 18 of the CCDC40 gene, results from a duplication of T at nucleotide position 2852, causing a translational frameshift with a predicted alternate stop codon (p.K952Efs*46). 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. -

Jul 06, 2017
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Lys952Glufs*46) in the CCDC40 gene. It is expected to result in an absent or disrupted protein product. This variant has been reported with a second pathogenic variant in an individual affected with primary ciliary dyskinesia (Invitae). ClinVar contains an entry for this variant (Variation ID: 241240). Loss-of-function variants in CCDC40 are known to be pathogenic (PMID: 21131974, 22693285, 23255504). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
1.1
Mutation Taster
=10/190
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Other links and lift over

dbSNP: rs878855042; hg19: chr17-78069080; API