NM_181426.2:c.1073_1076delCAAA

Variant names:

• chr3-180651491-TTTTG-T
• rs878855279
• NM_181426.2:c.1073_1076delCAAA

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_181426.2(CCDC39):​c.1073_1076delCAAA​(p.Thr358AsnfsTer2) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CCDC39 NM_181426.2 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.71
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 14

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000145075 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 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 3-180651491-TTTTG-T is Pathogenic according to our data. Variant chr3-180651491-TTTTG-T is described in CliVar as Pathogenic. Clinvar id is 242167.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-180651491-TTTTG-T is described in CliVar as Pathogenic. Clinvar id is 242167.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-180651491-TTTTG-T is described in CliVar as Pathogenic. Clinvar id is 242167.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-180651491-TTTTG-T is described in CliVar as Pathogenic. Clinvar id is 242167.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC39	NM_181426.2	c.1073_1076delCAAA	p.Thr358AsnfsTer2	frameshift_variant	Exon 9 of 20	ENST00000476379.6	NP_852091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC39	ENST00000476379.6	c.1073_1076delCAAA	p.Thr358AsnfsTer2	frameshift_variant	Exon 9 of 20	2	NM_181426.2	ENSP00000417960.2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Pathogenic:1

Mar 18, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change deletes 4 nucleotides from exon 9 of the CCDC39 mRNA (c.1073_1076delCAAA), causing a frameshift at codon 358. This creates a premature translational stop signal (p.Thr358Asnfs*2) and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, truncating variants in CCDC39 are known to be pathogenic (PMID: 21131972, 23255504). For these reasons, this variant has been classified as Pathogenic. -

CCDC39-related disorder Pathogenic:1

Mar 20, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CCDC39 c.1073_1076delCAAA variant is predicted to result in a frameshift and premature protein termination (p.Thr358Asnfs*2). To our knowledge, this variant has not been reported in the literature. This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in CCDC39 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.7
Mutation Taster		=10/190	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs878855279; hg19: chr3-180369279;