rs183413880

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_181426.2(CCDC39):c.1073C>T(p.Thr358Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00495 in 1,539,912 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0033 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0051 ( 26 hom. )

Consequence

CCDC39
NM_181426.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:11

Conservation

PhyloP100: 1.09

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:

ENSG00000145075 (HGNC:):

ENSG00000145075 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009362876).

BP6

Variant 3-180651495-G-A is Benign according to our data. Variant chr3-180651495-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 166806.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2, Likely_benign=6}. Variant chr3-180651495-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0033 (502/152048) while in subpopulation NFE AF= 0.00488 (332/67968). AF 95% confidence interval is 0.00445. There are 2 homozygotes in gnomad4. There are 238 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC39	NM_181426.2 link	c.1073C>T	p.Thr358Ile	missense_variant	Exon 9 of 20	ENST00000476379.6	NP_852091.1	Q9UFE4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC39	ENST00000476379.6 link	c.1073C>T	p.Thr358Ile	missense_variant	Exon 9 of 20	2	NM_181426.2	ENSP00000417960.2		Q9UFE4-1

Frequencies

GnomAD3 genomes

AF:

0.00330

AC:

502

AN:

151930

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000895

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00315

Gnomad ASJ

AF:

0.0176

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.000284

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00488

Gnomad OTH

AF:

0.00479

GnomAD3 exomes

AF:

0.00382

AC:

585

AN:

153056

Hom.:

AF XY:

0.00397

AC XY:

319

AN XY:

80256

show subpopulations

Gnomad AFR exome

AF:

0.00108

Gnomad AMR exome

AF:

0.00241

Gnomad ASJ exome

AF:

0.0184

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00207

Gnomad FIN exome

AF:

0.000601

Gnomad NFE exome

AF:

0.00471

Gnomad OTH exome

AF:

0.00532

GnomAD4 exome

AF:

0.00513

AC:

7125

AN:

1387864

Hom.:

Cov.:

AF XY:

0.00513

AC XY:

3514

AN XY:

684612

show subpopulations

Gnomad4 AFR exome

AF:

0.000873

Gnomad4 AMR exome

AF:

0.00277

Gnomad4 ASJ exome

AF:

0.0173

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00232

Gnomad4 FIN exome

AF:

0.000471

Gnomad4 NFE exome

AF:

0.00555

Gnomad4 OTH exome

AF:

0.00617

GnomAD4 genome

AF:

0.00330

AC:

502

AN:

152048

Hom.:

Cov.:

AF XY:

0.00320

AC XY:

238

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.000892

Gnomad4 AMR

AF:

0.00314

Gnomad4 ASJ

AF:

0.0176

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.000284

Gnomad4 NFE

AF:

0.00488

Gnomad4 OTH

AF:

0.00474

Alfa

AF:

0.00531

Hom.:

Bravo

AF:

0.00352

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00701

AC:

ESP6500AA

AF:

0.000848

AC:

ESP6500EA

AF:

0.00472

AC:

ExAC

AF:

0.00157

AC:

170

Asia WGS

AF:

0.000289

AC:

AN:

3474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 14, 2020	This variant is associated with the following publications: (PMID: 31213628) -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2025	CCDC39: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Primary ciliary dyskinesia 14

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 07, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Sep 28, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 28, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Primary ciliary dyskinesia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 02, 2025	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 05, 2016	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.36

CADD

Benign

4.6

DANN

Benign

0.91

DEOGEN2

Benign

0.0087

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.48

M_CAP

Benign

0.025

MetaRNN

Benign

0.0094

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.0

PrimateAI

Benign

0.35

PROVEAN

Benign

-2.2

REVEL

Benign

0.25

Sift

Benign

0.055

Sift4G

Benign

0.15

Polyphen

0.22

Vest4

0.22

MVP

0.73

MPC

0.072

ClinPred

0.0099

GERP RS

-4.4

Varity_R

0.036

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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