rs140505857

chr3-180642086-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_181426.2(CCDC39):c.1781C>T(p.Thr594Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000494 in 1,612,708 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00044 (1 hom.)
• Consequence: CCDC39 NM_181426.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:6
• Conservation: PhyloP100: 2.20

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.014485598).
• BP6: Variant 3-180642086-G-A is Benign according to our data. Variant chr3-180642086-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 242170.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Likely_benign=4}. Variant chr3-180642086-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00104 (159/152234) while in subpopulation AMR AF= 0.00392 (60/15296). AF 95% confidence interval is 0.00313. There are 0 homozygotes in gnomad4. There are 93 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC39	NM_181426.2	c.1781C>T	p.Thr594Ile	missense_variant	13/20	ENST00000476379.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC39	ENST00000476379.6	c.1781C>T	p.Thr594Ile	missense_variant	13/20	2	NM_181426.2	P2

Frequencies

GnomAD3 genomes AF: 0.00105 AC: 159 AN: 152116 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.000663 AC: 165 AN: 248922 Hom.: 0 AF XY: 0.000652 AC XY: 88 AN XY: 135038

Gnomad AFR exome AF: 0.000969

Gnomad AMR exome AF: 0.00238

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000514

Gnomad OTH exome AF: 0.00166

GnomAD4 exome AF: 0.000436 AC: 637 AN: 1460474 Hom.: 1 Cov.: 29 AF XY: 0.000439 AC XY: 319 AN XY: 726538

Gnomad4 AFR exome AF: 0.00152

Gnomad4 AMR exome AF: 0.00260

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000341

Gnomad4 OTH exome AF: 0.00128

GnomAD4 genome AF: 0.00104 AC: 159 AN: 152234 Hom.: 0 Cov.: 32 AF XY: 0.00125 AC XY: 93 AN XY: 74428

Gnomad4 AFR AF: 0.00144

Gnomad4 AMR AF: 0.00392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000487 Hom.: 1

Bravo AF: 0.00146

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000545 AC: 2

ESP6500EA AF: 0.000612 AC: 5

ExAC AF: 0.000480 AC: 58

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000657

EpiControl AF: 0.000712

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia 14 Uncertain:4

Uncertain significance, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Uncertain Significance - Insufficient Evidence, for Ciliary dyskinesia, primary, 14, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BS1 => Allele frequency is greater than expected for disorder. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 28, 2017	This 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Mar 04, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 28, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21131972, 22693285) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Primary ciliary dyskinesia Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 03, 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

Apr 14, 2016

Variant classified as Uncertain Significance - Favor Benign. The p.Thr594Ile var iant in CCDC39 has been reported in 1 Algerian individual with primary ciliary d yskinesia (a second pathogenic variant was not identified, Merveille 2011). This variant has also been identified in 0.2% (18/11538) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs 140505857). Isoleucine (Ile) at position 594 is not conserved in evolution, rais ing the possibility that a change at this position may be tolerated. In summary, while the clinical significance of the p.Thr594Ile variant is uncertain, its fr equency and lack of evolutionary conservation suggests that it is more likely to be benign. -

CCDC39-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 12, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.0051	T
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.094
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.12
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.17	T
Polyphen		0.99	D
Vest4		0.44
MVP		0.20
MPC		0.19
ClinPred		0.039	T
GERP RS		2.9
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

Other links and lift over

dbSNP: rs140505857; hg19: chr3-180359874;