Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_181426.2(CCDC39):c.2387T>G(p.Leu796*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,458,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CCDC39
NM_181426.2 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 8.09

Publications

0 publications found

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:

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

TTC14 links:

ENSG00000145075 (HGNC:):

ENSG00000145075 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 3-180616845-A-C is Pathogenic according to our data. Variant chr3-180616845-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 2753317.Status of the report is criteria_provided_single_submitter, 1 stars.

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

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

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CCDC39	ENST00000476379.6	TSL:2 MANE Select	c.2387T>G	p.Leu796*	stop_gained	Exon 17 of 20	ENSP00000417960.2
TTC14	ENST00000382584.8	TSL:1	c.1775-535A>C		intron	N/A	ENSP00000372027.4
CCDC39	ENST00000651046.1		c.2195T>G	p.Leu732*	stop_gained	Exon 16 of 19	ENSP00000499175.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1458048

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725436

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33380

American (AMR)

AF:

0.00

AC:

AN:

44480

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26068

East Asian (EAS)

AF:

0.00

AC:

AN:

39576

South Asian (SAS)

AF:

0.00

AC:

AN:

85904

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53048

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1109616

Other (OTH)

AF:

0.00

AC:

AN:

60220

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

0.80

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.97

PhyloP100

8.1

Vest4

0.12

GERP RS

5.0

PromoterAI

0.00080

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=29/171

disease causing (fs/PTC)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over