rs183413880

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 17/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T358A) has been classified as Uncertain significance.

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

Publications

8 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: G2P, ClinGen, 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

new If you want to explore the variant's impact on the transcript NM_181426.2, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 166806.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC39	NM_181426.2	MANE Select	c.1073C>T	p.Thr358Ile	missense	Exon 9 of 20	NP_852091.1	Q9UFE4-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CCDC39	ENST00000476379.6	TSL:2 MANE Select	c.1073C>T	p.Thr358Ile	missense	Exon 9 of 20	ENSP00000417960.2	Q9UFE4-1
CCDC39	ENST00000936067.1		c.980C>T	p.Thr327Ile	missense	Exon 8 of 19	ENSP00000606126.1
CCDC39	ENST00000651046.1		c.881C>T	p.Thr294Ile	missense	Exon 8 of 19	ENSP00000499175.1	A0A494C1Q3

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

GnomAD2 exomes

AF:

0.00382

AC:

585

AN:

153056

AF XY:

0.00397

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 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

African (AFR)

AF:

0.000873

AC:

AN:

30914

American (AMR)

AF:

0.00277

AC:

AN:

34284

Ashkenazi Jewish (ASJ)

AF:

0.0173

AC:

433

AN:

25028

East Asian (EAS)

AF:

0.00

AC:

AN:

35914

South Asian (SAS)

AF:

0.00232

AC:

177

AN:

76394

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

48878

Middle Eastern (MID)

AF:

0.0104

AC:

AN:

5676

European-Non Finnish (NFE)

AF:

0.00555

AC:

5955

AN:

1073120

Other (OTH)

AF:

0.00617

AC:

356

AN:

57656

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

331

661

992

1322

1653

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

264

528

792

1056

1320

<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:

0.00330

AC:

502

AN:

152048

Hom.:

Cov.:

AF XY:

0.00320

AC XY:

238

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.000892

AC:

AN:

41462

American (AMR)

AF:

0.00314

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.0176

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000284

AC:

AN:

10570

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00488

AC:

332

AN:

67968

Other (OTH)

AF:

0.00474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

110

138

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00456

Hom.:

Bravo

AF:

0.00352

Asia WGS

AF:

0.000289

AC:

AN:

3474

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Primary ciliary dyskinesia 14 (3)

not specified (2)

Primary ciliary dyskinesia (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.36

CADD

Benign

4.6

(source)

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

PhyloP100

1.1

PrimateAI

Benign

0.35

PROVEAN

Benign

-2.2

REVEL

Benign

0.25

Sift

Benign

0.055

Sift4G

Benign

0.15

Varity_R

0.036

Mutation Taster

=100/0

polymorphism

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over