chr3-180654860-CTG-C

Variant names:

• chr3-180654860-CTG-C
• rs773801386
• NM_181426.2:c.830_831delCA

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_181426.2(CCDC39):​c.830_831delCA​(p.Thr277ArgfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,604,204 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: CCDC39 NM_181426.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 1.36

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]

ENSG00000145075 (HGNC:):

ACMG classification

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 3-180654860-CTG-C is Pathogenic according to our data. Variant chr3-180654860-CTG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 242176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-180654860-CTG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC39	NM_181426.2	c.830_831delCA	p.Thr277ArgfsTer3	frameshift_variant	Exon 7 of 20	ENST00000476379.6	NP_852091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC39	ENST00000476379.6	c.830_831delCA	p.Thr277ArgfsTer3	frameshift_variant	Exon 7 of 20	2	NM_181426.2	ENSP00000417960.2

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152080 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000112 AC: 163 AN: 1452124 Hom.: 0 AF XY: 0.0000928 AC XY: 67 AN XY: 721748

Gnomad4 AFR exome AF: 0.0000605

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000137

Gnomad4 OTH exome AF: 0.000150

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 152080 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74300

Gnomad4 AFR AF: 0.0000241

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: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000529

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Pathogenic:3

Apr 24, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.830_831delCA pathogenic mutation, located in coding exon 7 of the CCDC39 gene, results from a deletion of two nucleotides at nucleotide positions 830 to 831, causing a translational frameshift with a predicted alternate stop codon (p.T277Rfs*3). This mutation has been identified in the homozygous and compound heterozygous state in several individuals with primary ciliary dyskinesia (Zariwala MA et al. Am J Hum Genet, 2013 Aug;93:336-45; Antony D et al. Hum Mutat, 2013 Mar;34:462-72; Davis SD et al. Am J Respir Crit Care Med, 2019 Jan;199:190-198). In addition to the clinical data presented in the literature, yhis 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. -

Aug 01, 2018

Yale Center for Mendelian Genomics, Yale University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 30, 2023

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.Thr277Argfs*3) 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 (rs773801386, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with primary ciliary dyskinesia (PMID: 2325550, 23891469). ClinVar contains an entry for this variant (Variation ID: 242176). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Primary ciliary dyskinesia 14 Pathogenic:3

Oct 26, 2018

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CCDC39 c.830_831delCA (p.Thr277ArgfsTer3) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Thr277ArgfsTer3 variant has been reported in three studies and was found in a total of six individuals with primary ciliary dyskinesia, including in two in a homozygous state and in four in a compound heterozygous state, although three of the compound heterozygous probands were members of the same family (Antony et al. 2013; Zariwala et al. 2013; Kim et al. 2014). The homozygous individual reported by Antony et al. (2013) also had three unaffected family members who carried the variant in a heterozygous state. Control data are unavailable for this variant. The highest reported frequency for the variant in the Exome Sequencing Project is 0.00828 in the African American population. However, this frequency is orders of magnitude higher than the highest frequency reported in the Exome Aggregation Consortium, where the p.Thr277ArgfsTer3 variant is found at a frequency of 0.00008 in the European (non-Finnish population). Due to the difficulty in calling indels, the frequency of this variant in the Exome Sequencing Project, which is inconsistent with the disease prevalence, is not considered reliable. Based on the evidence, including the potential impact of truncating frameshift variants, the p.Thr277ArgfsTer3 variant is considered to be likely pathogenic for primary ciliary dyskinesia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Aug 22, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CCDC39 c.830_831delCA (p.Thr277ArgfsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.830_831delCA has been reported in the literature in at-least one individual affected with Primary ciliary dyskinesia (example, Kim_2014). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 24498942). ClinVar contains an entry for this variant (Variation ID: 242176). Based on the evidence outlined above, the variant was classified as pathogenic. -

Mar 25, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Jul 17, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed with a pathogenic variant on the opposite allele (in trans) as well as in the homozygous state in association with primary ciliary dyskinesia in several patients in the published literature (PMID: 23891469, 23255504, 30067075); 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: 24498942, 31589614, 23255504, 31879361, 30067075, 35942088, 36809189, 36593399, 23891469) -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs773801386; hg19: chr3-180372648;