3-180616545-G-A

Position:

chr3-180616545-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_181426.2(CCDC39):c.2557C>T(p.Arg853Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000234 in 1,584,308 control chromosomes in the GnomAD database, including 1 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 1 hom. )

Consequence

CCDC39
NM_181426.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: -0.0120

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:

TTC14 (HGNC:24697): (tetratricopeptide repeat domain 14) Predicted to enable nucleic acid binding activity. [provided by Alliance of Genome Resources, Apr 2022]

TTC14 links:

ENSG00000145075 (HGNC:):

ENSG00000145075 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07119599).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC39	NM_181426.2 linkuse as main transcript	c.2557C>T	p.Arg853Cys	missense_variant	18/20	ENST00000476379.6	NP_852091.1	Q9UFE4-1
TTC14	NM_001288582.2 linkuse as main transcript	c.1775-835G>A		intron_variant			NP_001275511.1	Q96N46-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC39	ENST00000476379.6 linkuse as main transcript	c.2557C>T	p.Arg853Cys	missense_variant	18/20	2	NM_181426.2	ENSP00000417960.2		Q9UFE4-1

Frequencies

GnomAD3 genomes

AF:

0.000263

AC:

AN:

152014

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

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:

0.000378

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000427

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000354

AC:

AN:

229114

Hom.:

AF XY:

0.000371

AC XY:

AN XY:

123972

show subpopulations

Gnomad AFR exome

AF:

0.000275

Gnomad AMR exome

AF:

0.0000649

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000309

Gnomad FIN exome

AF:

0.000147

Gnomad NFE exome

AF:

0.000595

Gnomad OTH exome

AF:

0.000180

GnomAD4 exome

AF:

0.000231

AC:

331

AN:

1432294

Hom.:

Cov.:

AF XY:

0.000239

AC XY:

170

AN XY:

710348

show subpopulations

Gnomad4 AFR exome

AF:

0.000185

Gnomad4 AMR exome

AF:

0.0000489

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000174

Gnomad4 FIN exome

AF:

0.000344

Gnomad4 NFE exome

AF:

0.000254

Gnomad4 OTH exome

AF:

0.000186

GnomAD4 genome

AF:

0.000263

AC:

AN:

152014

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74260

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000378

Gnomad4 NFE

AF:

0.000427

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000484

Hom.:

Bravo

AF:

0.000268

ESP6500AA

AF:

0.000274

AC:

ESP6500EA

AF:

0.000615

AC:

ExAC

AF:

0.000414

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 14

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -

Primary ciliary dyskinesia

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 27, 2022	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 853 of the CCDC39 protein (p.Arg853Cys). This variant is present in population databases (rs201097154, gnomAD 0.06%). 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: 228476). 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. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 10, 2022	This alteration is classified as likely 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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 09, 2015

The p.Arg853Cys variant in CCDC39 has not been previously reported in individual s with pulmonary disease, but has been identified in 41/53056 European chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs201097154). Computational prediction tools and conservation analysis sugge st that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significan ce of the p.Arg853Cys variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.0038

.;T

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.81

T;T

M_CAP

Benign

0.085

MetaRNN

Benign

0.071

T;T

MetaSVM

Benign

-0.77

MutationAssessor

Benign

1.7

.;L

PrimateAI

Benign

0.21

PROVEAN

Uncertain

-2.7

D;N

REVEL

Uncertain

0.38

Sift

Benign

0.12

T;T

Sift4G

Benign

0.083

T;T

Polyphen

0.97

.;D

Vest4

0.39

MVP

0.60

MPC

0.29

ClinPred

0.068

GERP RS

-0.88

Varity_R

0.051

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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