3-180616845-A-T

Variant names:

• chr3-180616845-A-T
• NM_181426.2:c.2387T>A
• CCDC39 p.Leu796*

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_181426.2(CCDC39):​c.2387T>A​(p.Leu796*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CCDC39 NM_181426.2 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.09
• 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]

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

Our verdict: Pathogenic. The variant received 10 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181426.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC39	NM_181426.2	MANE Select	c.2387T>A	p.Leu796*	stop_gained	Exon 17 of 20	NP_852091.1	Q9UFE4-1
	TTC14	NM_001288582.2		c.1775-535A>T		intron	N/A	NP_001275511.1	Q96N46-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC39	ENST00000476379.6	TSL:2 MANE Select	c.2387T>A	p.Leu796*	stop_gained	Exon 17 of 20	ENSP00000417960.2	Q9UFE4-1
	TTC14	ENST00000382584.8	TSL:1	c.1775-535A>T		intron	N/A	ENSP00000372027.4	Q96N46-2
	CCDC39	ENST00000936067.1		c.2294T>A	p.Leu765*	stop_gained	Exon 16 of 19	ENSP00000606126.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	41
DANN	Uncertain	0.99
Eigen	Pathogenic	0.80
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.97	D
PhyloP100		8.1
PromoterAI		-0.0075	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=29/171	disease causing (fs/PTC)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr3-180334633;

COSMIC: COSV105082443;

COSMIC: COSV105082443;