rs201794121

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_181426.2(CCDC39):c.83A>C(p.Glu28Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000475 in 1,613,522 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00050 ( 1 hom. )

Consequence

CCDC39
NM_181426.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 3.93

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC39	NM_181426.2 linkuse as main transcript	c.83A>C	p.Glu28Ala	missense_variant	1/20	ENST00000476379.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC39	ENST00000476379.6 linkuse as main transcript	c.83A>C	p.Glu28Ala	missense_variant	1/20	2	NM_181426.2	P2	Q9UFE4-1

Frequencies

GnomAD3 genomes

AF:

0.000243

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

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:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000456

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000249

AC:

AN:

249232

Hom.:

AF XY:

0.000266

AC XY:

AN XY:

135214

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:

0.0000464

Gnomad NFE exome

AF:

0.000540

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000499

AC:

729

AN:

1461400

Hom.:

Cov.:

AF XY:

0.000415

AC XY:

302

AN XY:

727006

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000936

Gnomad4 NFE exome

AF:

0.000637

Gnomad4 OTH exome

AF:

0.000215

GnomAD4 genome

AF:

0.000243

AC:

AN:

152122

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.0000966

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.000456

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000436

Hom.:

Bravo

AF:

0.000246

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000963

AC:

ExAC

AF:

0.000256

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 11, 2019	The p.E28A variant (also known as c.83A>C), located in coding exon 1 of the CCDC39 gene, results from an A to C substitution at nucleotide position 83. The glutamic acid at codon 28 is replaced by alanine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 05, 2022	This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 28 of the CCDC39 protein (p.Glu28Ala). This variant is present in population databases (rs201794121, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with CCDC39-related conditions. ClinVar contains an entry for this variant (Variation ID: 242177). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Primary ciliary dyskinesia 14

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

May 21, 2020

A heterozygous missense variant was identified, NM_181426.2(CCDC39):c.83A>C in exon 1 of the CCDC39 gene. This substitution is predicted to create a major amino acid change from a glutamic acid to an alanine at position 28 of the protein; NP_852091.1(CCDC39):p.(Glu28Ala). The glutamic acid at this position has very high conservation (100 vertebrates, UCSC), and is located within the coiled coil domain (PDB). In silico software predicts this variant to be damaging (PolyPhen2, PROVEAN, Mutation Assessor). The variant is present in the gnomAD population database at a global population frequency of 0.02% (70 heterozygotes, 0 homozygotes) with a European sub-population frequency of 0.05%. This variant has been previously reported as a VUS (ClinVar). Based on information available at the time of curation, this variant has been classified as a VUS. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.12

Cadd

Pathogenic

Dann

Uncertain

0.99

DEOGEN2

Benign

0.032

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.83

M_CAP

Benign

0.011

MetaRNN

Uncertain

0.48

MetaSVM

Benign

-0.71

MutationAssessor

Uncertain

2.8

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-3.1

REVEL

Benign

0.093

Sift

Benign

0.091

Sift4G

Benign

0.37

Polyphen

0.85

Vest4

0.65

MVP

0.49

MPC

0.17

ClinPred

0.35

GERP RS

5.6

Varity_R

0.23

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