chr3-180659741-G-C

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.545C>G(p.Thr182Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0318 in 1,610,888 control chromosomes in the GnomAD database, including 971 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 73 hom., cov: 32)

Exomes 𝑓: 0.032 ( 898 hom. )

Consequence

CCDC39
NM_181426.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 5.82

Publications

11 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=0.0033574104).

BP6

Variant 3-180659741-G-C is Benign according to our data. Variant chr3-180659741-G-C is described in ClinVar as Benign. ClinVar VariationId is 162844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0251 (3828/152228) while in subpopulation NFE AF = 0.0391 (2660/67974). AF 95% confidence interval is 0.0379. There are 73 homozygotes in GnomAd4. There are 1820 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 73 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC39	NM_181426.2 link	c.545C>G	p.Thr182Ser	missense_variant	Exon 5 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.545C>G	p.Thr182Ser	missense_variant	Exon 5 of 20	2	NM_181426.2	ENSP00000417960.2		Q9UFE4-1

Frequencies

GnomAD3 genomes

AF:

0.0252

AC:

3828

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00668

Gnomad AMI

AF:

0.128

Gnomad AMR

AF:

0.0221

Gnomad ASJ

AF:

0.00692

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.00476

Gnomad FIN

AF:

0.0331

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0391

Gnomad OTH

AF:

0.0177

GnomAD2 exomes

AF:

0.0241

AC:

5985

AN:

248098

AF XY:

0.0239

show subpopulations

Gnomad AFR exome

AF:

0.00530

Gnomad AMR exome

AF:

0.0152

Gnomad ASJ exome

AF:

0.00767

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0307

Gnomad NFE exome

AF:

0.0384

Gnomad OTH exome

AF:

0.0278

GnomAD4 exome

AF:

0.0325

AC:

47386

AN:

1458660

Hom.:

898

Cov.:

AF XY:

0.0320

AC XY:

23217

AN XY:

725682

show subpopulations

African (AFR)

AF:

0.00568

AC:

190

AN:

33442

American (AMR)

AF:

0.0150

AC:

672

AN:

44656

Ashkenazi Jewish (ASJ)

AF:

0.00858

AC:

224

AN:

26100

East Asian (EAS)

AF:

0.00

AC:

AN:

39538

South Asian (SAS)

AF:

0.00583

AC:

502

AN:

86070

European-Finnish (FIN)

AF:

0.0299

AC:

1580

AN:

52778

Middle Eastern (MID)

AF:

0.00592

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.0384

AC:

42638

AN:

1110028

Other (OTH)

AF:

0.0256

AC:

1546

AN:

60302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

2099

4197

6296

8394

10493

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1502

3004

4506

6008

7510

<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:

0.0251

AC:

3828

AN:

152228

Hom.:

Cov.:

AF XY:

0.0244

AC XY:

1820

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.00666

AC:

277

AN:

41570

American (AMR)

AF:

0.0221

AC:

337

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00692

AC:

AN:

3466

East Asian (EAS)

AF:

0.000385

AC:

AN:

5196

South Asian (SAS)

AF:

0.00476

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0331

AC:

351

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0391

AC:

2660

AN:

67974

Other (OTH)

AF:

0.0175

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

196

393

589

786

982

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<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:

0.0310

Hom.:

Bravo

AF:

0.0235

TwinsUK

AF:

0.0388

AC:

144

ALSPAC

AF:

0.0381

AC:

147

ESP6500AA

AF:

0.00936

AC:

ESP6500EA

AF:

0.0323

AC:

263

ExAC

AF:

0.0245

AC:

2958

Asia WGS

AF:

0.00115

AC:

AN:

3476

EpiCase

AF:

0.0391

EpiControl

AF:

0.0321

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Thr182Ser in exon 5 of CCDC39: This variant is not expected to have clinical sig nificance because it has been identified in 3.2% (263/8154) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs112738198). -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary ciliary dyskinesia

Benign:2

Sep 30, 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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Primary ciliary dyskinesia 14

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.041

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.54

MetaRNN

Benign

0.0034

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

PhyloP100

5.8

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.11

Sift

Uncertain

0.022

Sift4G

Benign

0.18

Polyphen

0.98

Vest4

0.15

MutPred

0.14

Gain of glycosylation at T182 (P = 0.096);

MPC

0.14

ClinPred

0.036

GERP RS

4.0

Varity_R

0.15

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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