rs115545935

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_181426.2(CCDC39):ā€‹c.1433A>Gā€‹(p.Gln478Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00554 in 1,612,170 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.0031 ( 2 hom., cov: 32)
Exomes š‘“: 0.0058 ( 37 hom. )

Consequence

CCDC39
NM_181426.2 missense

Scores

2
17

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 1.77
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.003198415).
BP6
Variant 3-180647173-T-C is Benign according to our data. Variant chr3-180647173-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 226483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-180647173-T-C is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00309 (471/152196) while in subpopulation NFE AF= 0.00561 (381/67956). AF 95% confidence interval is 0.00514. There are 2 homozygotes in gnomad4. There are 201 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/exons MANE Protein UniProt
CCDC39NM_181426.2 linkuse as main transcriptc.1433A>G p.Gln478Arg missense_variant 11/20 ENST00000476379.6 NP_852091.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CCDC39ENST00000476379.6 linkuse as main transcriptc.1433A>G p.Gln478Arg missense_variant 11/202 NM_181426.2 ENSP00000417960 P2Q9UFE4-1

Frequencies

GnomAD3 genomes
AF:
0.00310
AC:
471
AN:
152078
Hom.:
2
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00118
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000722
Gnomad ASJ
AF:
0.00547
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000829
Gnomad FIN
AF:
0.0000942
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00562
Gnomad OTH
AF:
0.00239
GnomAD3 exomes
AF:
0.00285
AC:
705
AN:
247522
Hom.:
2
AF XY:
0.00296
AC XY:
397
AN XY:
134322
show subpopulations
Gnomad AFR exome
AF:
0.00110
Gnomad AMR exome
AF:
0.000555
Gnomad ASJ exome
AF:
0.00449
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00132
Gnomad FIN exome
AF:
0.000513
Gnomad NFE exome
AF:
0.00500
Gnomad OTH exome
AF:
0.00200
GnomAD4 exome
AF:
0.00579
AC:
8454
AN:
1459974
Hom.:
37
Cov.:
31
AF XY:
0.00556
AC XY:
4040
AN XY:
726200
show subpopulations
Gnomad4 AFR exome
AF:
0.000718
Gnomad4 AMR exome
AF:
0.000650
Gnomad4 ASJ exome
AF:
0.00479
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00161
Gnomad4 FIN exome
AF:
0.000451
Gnomad4 NFE exome
AF:
0.00695
Gnomad4 OTH exome
AF:
0.00649
GnomAD4 genome
AF:
0.00309
AC:
471
AN:
152196
Hom.:
2
Cov.:
32
AF XY:
0.00270
AC XY:
201
AN XY:
74418
show subpopulations
Gnomad4 AFR
AF:
0.00118
Gnomad4 AMR
AF:
0.000721
Gnomad4 ASJ
AF:
0.00547
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00104
Gnomad4 FIN
AF:
0.0000942
Gnomad4 NFE
AF:
0.00561
Gnomad4 OTH
AF:
0.00237
Alfa
AF:
0.00494
Hom.:
5
Bravo
AF:
0.00303
TwinsUK
AF:
0.00378
AC:
14
ALSPAC
AF:
0.00441
AC:
17
ESP6500AA
AF:
0.00168
AC:
6
ESP6500EA
AF:
0.00567
AC:
46
ExAC
AF:
0.00273
AC:
330
Asia WGS
AF:
0.00144
AC:
5
AN:
3476
EpiCase
AF:
0.00453
EpiControl
AF:
0.00499

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:4
Likely benign, criteria provided, single submitterclinical testingGeneDxJan 19, 2021This variant is associated with the following publications: (PMID: 25118008) -
Likely benign, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsMay 30, 2017- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMay 01, 2024CCDC39: BP4, BS2 -
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
not specified Benign:3
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineFeb 21, 2013Gln478Arg in exon 11 of CCDC39: This variant is not expected to have clinical si gnificance because it has been identified in 4.5% (8/178) of English and Scottis h chromosomes from a broad population by the 1000 Genomes Project (http://www.nc bi.nlm.nih.gov/projects/SNP; dbSNP rs115545935). -
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Sep 19, 2015- -
Primary ciliary dyskinesia Benign:2
Benign, criteria provided, single submitterclinical testingAmbry GeneticsFeb 14, 2017This 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. -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2024- -
Primary ciliary dyskinesia 14 Benign:2
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesOct 02, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.093
BayesDel_addAF
Benign
-0.51
T
BayesDel_noAF
Benign
-0.50
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.00068
T
Eigen
Benign
0.078
Eigen_PC
Benign
0.097
FATHMM_MKL
Uncertain
0.81
D
LIST_S2
Benign
0.74
T
M_CAP
Benign
0.0092
T
MetaRNN
Benign
0.0032
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
2.0
M
MutationTaster
Benign
0.79
N;N
PrimateAI
Benign
0.36
T
PROVEAN
Benign
-0.28
N
REVEL
Benign
0.032
Sift
Benign
0.069
T
Sift4G
Benign
0.34
T
Polyphen
0.93
P
Vest4
0.13
MVP
0.50
MPC
0.066
ClinPred
0.026
T
GERP RS
2.8
Varity_R
0.071

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.

Other links and lift over

dbSNP: rs115545935; hg19: chr3-180364961; COSMIC: COSV99071594; API