rs587778821

Positions:

• chr3-180616872-TTAC-TA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_181426.2(CCDC39):​c.2357_2359delGTAinsT​(p.Ser786fs) variant causes a frameshift, stop gained 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, stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 4.19

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]

TTC14 (HGNC:24697): (tetratricopeptide repeat domain 14) Predicted to enable nucleic acid binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000145075 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 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 3-180616873-TAC-A is Pathogenic according to our data. Variant chr3-180616873-TAC-A is described in ClinVar as [Pathogenic]. Clinvar id is 65994.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC39	NM_181426.2	c.2357_2359delGTAinsT	p.Ser786fs	frameshift_variant, stop_gained	17/20	ENST00000476379.6	NP_852091.1
TTC14	NM_001288582.2	c.1775-507_1775-505delTACinsA		intron_variant			NP_001275511.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC39	ENST00000476379.6	c.2357_2359delGTAinsT	p.Ser786fs	frameshift_variant, stop_gained	17/20	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:3

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia 14 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2011	- -
Pathogenic, no assertion criteria provided	curation	GeneReviews	Sep 15, 2011	- -

Primary ciliary dyskinesia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 17, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 631917). This premature translational stop signal has been observed in individual(s) with primary ciliary dyskinesia (PMID: 21131972). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This sequence change creates a premature translational stop signal (p.Ser786Ilefs*33) 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). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs587778821; hg19: chr3-180334661;