rs397515393

Positions:

chr17-80039965-GC-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_017950.4(CCDC40):c.248del(p.Ala83ValfsTer84) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000563 in 1,600,206 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00059 ( 0 hom. )

Consequence

CCDC40
NM_017950.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:19O:1

Conservation

PhyloP100: -4.80

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]

CCDC40 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 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 17-80039965-GC-G is Pathogenic according to our data. Variant chr17-80039965-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 31069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80039965-GC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CCDC40	NM_017950.4 linkuse as main transcript	c.248del	p.Ala83ValfsTer84	frameshift_variant	3/20	ENST00000397545.9	NP_060420.2
CCDC40	NM_001243342.2 linkuse as main transcript	c.248del	p.Ala83ValfsTer84	frameshift_variant	3/18		NP_001230271.1
CCDC40	NM_001330508.2 linkuse as main transcript	c.248del	p.Ala83ValfsTer84	frameshift_variant	3/11		NP_001317437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC40	ENST00000397545.9 linkuse as main transcript	c.248del	p.Ala83ValfsTer84	frameshift_variant	3/20	5	NM_017950.4	ENSP00000380679	P2	Q4G0X9-1

Frequencies

GnomAD3 genomes

AF:

0.000270

AC:

AN:

152026

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000485

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000441

AC:

109

AN:

247240

Hom.:

AF XY:

0.000380

AC XY:

AN XY:

134340

show subpopulations

Gnomad AFR exome

AF:

0.000194

Gnomad AMR exome

AF:

0.000232

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.000838

Gnomad OTH exome

AF:

0.000496

GnomAD4 exome

AF:

0.000594

AC:

860

AN:

1448062

Hom.:

Cov.:

AF XY:

0.000576

AC XY:

415

AN XY:

721066

show subpopulations

Gnomad4 AFR exome

AF:

0.000181

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000752

Gnomad4 OTH exome

AF:

0.000234

GnomAD4 genome

AF:

0.000269

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000289

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000485

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000450

Hom.:

Bravo

AF:

0.000321

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000818

EpiControl

AF:

0.000711

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 15

Pathogenic:7Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 21, 2022	- -
not provided, no classification provided	phenotyping only	GenomeConnect - Brain Gene Registry	-	Variant interpreted as Pathogenic and reported on 01-14-2020 by Lab PreventionGenetics. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 04, 2018	Based on the potential impact of frameshift variants and the evidence, the p.Trp77LeufsTer13 variant is classified as likely pathogenic for Desbuquois dysplasia. -
Pathogenic, no assertion criteria provided	curation	GeneReviews	Sep 15, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Apr 01, 2021	CCDC40 c.248delC has been identified in the homozygous or compound heterozygous state in many individuals with primary ciliary dyskinesia 15. This CCDC40 variant (rs397515393) is rare (<0.1%) in a large population dataset (gnomAD: 119/278616 total alleles; 0.04%; no homozygotes) and has been reported in ClinVar (Variation ID: 31069). This frameshift variant is predicted to result in a premature stop codon in exon 3 of 20 likely leading to nonsense-mediated decay and lack of protein production. We consider this variant to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	May 11, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 28, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2013	- -

not provided

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 14, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 25, 2022	Frameshift 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: 29363216, 23891469, 22499950, 21131974, 23255504, 31772028, 31879361, 31980526, 25619595, 22693285) -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 22, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Mar 01, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Primary ciliary dyskinesia

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	This sequence change creates a premature translational stop signal (p.Ala83Valfs*84) in the CCDC40 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CCDC40 are known to be pathogenic (PMID: 21131974, 22693285, 23255504). This variant is present in population databases (rs397515393, gnomAD 0.08%). This premature translational stop signal has been observed in individuals with primary ciliary dyskinesia (PMID: 21131974, 22693285, 23255504, 25619595). ClinVar contains an entry for this variant (Variation ID: 31069). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	Jan 15, 2019	- -
Likely pathogenic, no assertion criteria provided	literature only	Yale Center for Mendelian Genomics, Yale University	Aug 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 06, 2023	The c.248delC pathogenic mutation, located in coding exon 3 of the CCDC40 gene, results from a deletion of one nucleotide at nucleotide position 248, causing a translational frameshift with a predicted alternate stop codon (p.A83Vfs*84). This mutation has been identified in multiple homozygous and compound heterozygous individuals with primary ciliary dyskinesia (Becker-Heck A et al. Nat. Genet., 2011 Jan;43:79-84; Antony D et al. Hum. Mutat., 2013 Mar;34:462-72). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 22, 2024	The p.Ala83ValfsX84 variant in CCDC40 has been previously reported in 19 homozygous and 7 compound heterozygous individuals with primary ciliary dyskinesia (PCD) and segregated with disease in 1 homozygous affected relative (Becker-Heck 2011 PMID: 21131974, Nakhleh 2012 PMID: 22499950, Antony 2013 PMID: 23255504, Zariwala 2013 PMID: 23891469). This variant has been identified in 0.074% (860/1167354) of non-Finnish European chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive allele frequency. This variant has also been reported in ClinVar (Variation ID 31069). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 83 and leads to a premature termination codon 84 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Functional studies indicate that loss of CCDC40 function results in abnormal cilia structure and motility (Becker-Heck 2011 PMID: 21131974). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive primary ciliary dyskinesia. ACMG/AMP Criteria applied: PVS1, PM3_VeryStrong, PM2_Supporting, PP1. -

CCDC40-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 13, 2024

The CCDC40 c.248delC variant is predicted to result in a frameshift and premature protein termination (p.Ala83Valfs*84). This variant has been reported in the compound heterozygous and homozygous states in many unrelated individuals with primary ciliary dyskinesia (Becker-Heck et al. 2011. PubMed ID: 21131974; Zariwala et al. 2013. PubMed ID: 23891469, Table S1, Blanchon et al. 2019. PubMed ID: 31772028; Fassad et al. 2019. PubMed ID: 31879361; Hou et al. 2020. PubMed ID: 31980526). This variant is reported in 0.078% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.18

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over