3-180661985-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_181426.2(CCDC39):c.233G>A(p.Arg78His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00647 in 1,552,978 control chromosomes in the GnomAD database, including 60 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R78C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0047 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0067 ( 55 hom. )

Consequence

CCDC39
NM_181426.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.724

Publications

6 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 Gene-Disease associations (from GenCC):

primary ciliary dyskinesia 14
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CCDC39 links:

ENSG00000145075 (HGNC:):

ENSG00000145075 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0032339096).

BP6

Variant 3-180661985-C-T is Benign according to our data. Variant chr3-180661985-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 221189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00468 (713/152196) while in subpopulation SAS AF = 0.0183 (88/4820). AF 95% confidence interval is 0.0152. There are 5 homozygotes in GnomAd4. There are 358 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC39	NM_181426.2 link	c.233G>A	p.Arg78His	missense_variant	Exon 3 of 20	ENST00000476379.6	NP_852091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC39	ENST00000476379.6 link	c.233G>A	p.Arg78His	missense_variant	Exon 3 of 20	2	NM_181426.2	ENSP00000417960.2

Frequencies

GnomAD3 genomes

AF:

0.00469

AC:

713

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00126

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.000721

Gnomad ASJ

AF:

0.0147

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.0182

Gnomad FIN

AF:

0.00877

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00587

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00722

AC:

1159

AN:

160442

AF XY:

0.00804

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.00101

Gnomad ASJ exome

AF:

0.0185

Gnomad EAS exome

AF:

0.000266

Gnomad FIN exome

AF:

0.00842

Gnomad NFE exome

AF:

0.00636

Gnomad OTH exome

AF:

0.00535

GnomAD4 exome

AF:

0.00666

AC:

9329

AN:

1400782

Hom.:

Cov.:

AF XY:

0.00690

AC XY:

4769

AN XY:

691044

show subpopulations

African (AFR)

AF:

0.00113

AC:

AN:

31762

American (AMR)

AF:

0.00112

AC:

AN:

35736

Ashkenazi Jewish (ASJ)

AF:

0.0161

AC:

405

AN:

25174

East Asian (EAS)

AF:

0.000111

AC:

AN:

36166

South Asian (SAS)

AF:

0.0177

AC:

1400

AN:

79002

European-Finnish (FIN)

AF:

0.00820

AC:

407

AN:

49640

Middle Eastern (MID)

AF:

0.00211

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.00618

AC:

6669

AN:

1079500

Other (OTH)

AF:

0.00613

AC:

356

AN:

58106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

451

902

1352

1803

2254

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

274

548

822

1096

1370

<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

AF:

0.00468

AC:

713

AN:

152196

Hom.:

Cov.:

AF XY:

0.00481

AC XY:

358

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.00125

AC:

AN:

41546

American (AMR)

AF:

0.000720

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.0147

AC:

AN:

3472

East Asian (EAS)

AF:

0.000385

AC:

AN:

5192

South Asian (SAS)

AF:

0.0183

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00877

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00587

AC:

399

AN:

67970

Other (OTH)

AF:

0.00284

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

112

149

186

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00563

Hom.:

Bravo

AF:

0.00364

TwinsUK

AF:

0.00782

AC:

ALSPAC

AF:

0.00752

AC:

ESP6500AA

AF:

0.00138

AC:

ESP6500EA

AF:

0.00738

AC:

ExAC

AF:

0.00479

AC:

502

Asia WGS

AF:

0.00549

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Nov 06, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 31213628) -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CCDC39: BP4, BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Primary ciliary dyskinesia

Benign:2

Jul 19, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary ciliary dyskinesia 14

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.38

CADD

Benign

8.5

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.0040

T;.

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.59

T;.

MetaRNN

Benign

0.0032

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

-0.23

N;.

PhyloP100

0.72

PrimateAI

Benign

0.22

PROVEAN

Benign

-1.7

N;N

REVEL

Benign

0.12

Sift

Benign

0.42

T;T

Sift4G

Benign

0.68

T;.

Polyphen

0.0070

B;.

Vest4

0.21

MVP

0.65

MPC

0.062

ClinPred

0.0057

GERP RS

2.6

Varity_R

0.039

Mutation Taster

=100/0

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over