rs201780665

chr3-180642072-G-Achr3-180642072-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_181426.2(CCDC39):c.1795C>T(p.Arg599Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000875 in 1,611,134 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R599R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000092 ( 0 hom. )

Consequence

CCDC39
NM_181426.2 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1

Conservation

PhyloP100: 0.885

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 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 3-180642072-G-A is Pathogenic according to our data. Variant chr3-180642072-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 455014.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=3, Uncertain_significance=1}. Variant chr3-180642072-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC39	NM_181426.2 linkuse as main transcript	c.1795C>T	p.Arg599Ter	stop_gained	13/20	ENST00000476379.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC39	ENST00000476379.6 linkuse as main transcript	c.1795C>T	p.Arg599Ter	stop_gained	13/20	2	NM_181426.2	P2	Q9UFE4-1

Frequencies

GnomAD3 genomes

AF:

0.0000461

AC:

AN:

151956

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.0000883

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000765

AC:

AN:

248382

Hom.:

AF XY:

0.0000594

AC XY:

AN XY:

134776

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000160

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000918

AC:

134

AN:

1459060

Hom.:

Cov.:

AF XY:

0.0000840

AC XY:

AN XY:

725796

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000384

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000118

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152074

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74338

show subpopulations

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:

0.0000883

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000648

Hom.:

Bravo

AF:

0.0000378

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.0000993

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 03, 2024	This sequence change creates a premature translational stop signal (p.Arg599*) 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 (rs201780665, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with primary ciliary dyskinesia (PMID: 23255504, 24498942). ClinVar contains an entry for this variant (Variation ID: 455014). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 11, 2021	The p.R599* pathogenic mutation (also known as c.1795C>T), located in coding exon 13 of the CCDC39 gene, results from a C to T substitution at nucleotide position 1795. This changes the amino acid from an arginine to a stop codon within coding exon 13. This mutation has been reported in one homozgyous and two compound heterozygous individuals with primary ciliary dyskiensia (Antony D et al. Hum Mutat, 2013 Mar;34:462-72; Davis SD et al. Am J Respir Crit Care Med, 2019 01;199:190-198). In addition to the clinical data presented in the literature, this 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. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

AiLife Diagnostics, AiLife Diagnostics

Jan 21, 2022

- -

Primary ciliary dyskinesia 14

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota

Nov 24, 2020

- -

Ellis-van Creveld syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Rare Disease Group, Clinical Genetics, Karolinska Institutet

May 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.53

Cadd

Pathogenic

Dann

Uncertain

0.99

Eigen

Benign

0.18

Eigen_PC

Benign

-0.046

FATHMM_MKL

Benign

0.71

MutationTaster

Benign

1.0

A;A

Vest4

0.35

GERP RS

1.7

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over