Genetic Variant NM_181426.2:c.2190delA (chr3-180619333-CT-C) – ACMG Classification: Pathogenic (18 pts)

Variant summary

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

The NM_181426.2(CCDC39):c.2190delA(p.Glu731AsnfsTer31) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,539,432 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 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

CCDC39
NM_181426.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 1.58

Variant links:

Genes affected

CCDC39 (HGNC:25244): (coiled-coil domain 39 molecular ruler complex subunit) The protein encoded by this gene is involved in the motility of cilia and flagella. The encoded protein is essential for the assembly of dynein regulatory and inner dynein arm complexes, which regulate ciliary beat. Defects in this gene are a cause of primary ciliary dyskinesia type 14 (CILD14). [provided by RefSeq, Jul 2011]

CCDC39 links:

ENSG00000145075 (HGNC:):

ENSG00000145075 links:

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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 3-180619333-CT-C is Pathogenic according to our data. Variant chr3-180619333-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 65950.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
CCDC39	NM_181426.2 link	c.2190delA	p.Glu731AsnfsTer31	frameshift_variant	Exon 16 of 20	ENST00000476379.6	NP_852091.1	Q9UFE4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC39	ENST00000476379.6 link	c.2190delA	p.Glu731AsnfsTer31	frameshift_variant	Exon 16 of 20	2	NM_181426.2	ENSP00000417960.2		Q9UFE4-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151814

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000257

AC:

AN:

155898

Hom.:

AF XY:

0.0000244

AC XY:

AN XY:

81928

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000655

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1387618

Hom.:

Cov.:

AF XY:

0.0000102

AC XY:

AN XY:

684896

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000400

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000140

Gnomad4 OTH exome

AF:

0.0000174

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151814

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74160

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 14

Pathogenic:4

Jan 01, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 15, 2011

GeneReviews

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

- -

May 22, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000065950 / PMID: 21131972). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Apr 03, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CCDC39 c.2190del; p.Glu731AsnfsTer31 variant (rs587778820) is reported in both the homozygous and compound heterozygous states in several individuals with primary ciliary dyskinesia (Blanchon 2020, Boaretto 2016, Mani 2020, Merveille 2011). This variant is also reported in ClinVar (Variation ID: 65950). It is only found on five alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Blanchon S et al. Deep phenotyping, including quantitative ciliary beating parameters, and extensive genotyping in primary ciliary dyskinesia. J Med Genet. 2020 Apr;57(4):237-244. PMID: 31772028. Boaretto F et al. Diagnosis of Primary Ciliary Dyskinesia by a Targeted Next-Generation Sequencing Panel: Molecular and Clinical Findings in Italian Patients. J Mol Diagn. 2016 Nov;18(6):912-922. PMID: 27637300. Mani R et al. Primary ciliary dyskinesia gene contribution in Tunisia: Identification of a major Mediterranean allele. Hum Mutat. 2020 Jan;41(1):115-121. PMID: 31469207. Merveille AC et al. CCDC39 is required for assembly of inner dynein arms and the dynein regulatory complex and for normal ciliary motility in humans and dogs. Nat Genet. 2011 Jan;43(1):72-8. PMID: 21131972. -

Primary ciliary dyskinesia

Pathogenic:2

Jun 29, 2024

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.Glu731Asnfs*31) in the CCDC39 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CCDC39 are known to be pathogenic (PMID: 21131972, 23255504). This variant is present in population databases (rs587778820, gnomAD 0.005%). This premature translational stop signal has been observed in individuals with primary ciliary dyskinesia (PMID: 21131972, 27637300, 30067075). ClinVar contains an entry for this variant (Variation ID: 65950). For these reasons, this variant has been classified as Pathogenic. -

Mar 11, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2190delA pathogenic mutation, located in coding exon 16 of the CCDC39 gene, results from a deletion of one nucleotide at nucleotide position 2190, causing a translational frameshift with a predicted alternate stop codon (p.E731Nfs*31). This variant has been reported in several homozygous or compound heterozygous individuals with primary ciliary dyskinesia (Merveille AC et al. Nat Genet, 2011 Jan;43:72-8; Blanchon S et al. J Med Genet, 2020 04;57:237-244). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

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