rs6769457

chr3-180648168-G-Achr3-180648168-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_181426.2(CCDC39):c.1359C>T(p.Ser453=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.239 in 1,604,550 control chromosomes in the GnomAD database, including 54,550 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (11653 hom., cov: 31)
  • Exomes 𝑓: 0.23 (42897 hom.)
• Consequence: CCDC39 NM_181426.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.458

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 3-180648168-G-A is Benign according to our data. Variant chr3-180648168-G-A is described in ClinVar as [Benign]. Clinvar id is 162842.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-180648168-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.458 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.638 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC39	NM_181426.2	c.1359C>T	p.Ser453=	synonymous_variant	10/20	ENST00000476379.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC39	ENST00000476379.6	c.1359C>T	p.Ser453=	synonymous_variant	10/20	2	NM_181426.2	P2

Frequencies

GnomAD3 genomes AF: 0.340 AC: 51594 AN: 151802 Hom.: 11614 Cov.: 31

Gnomad AFR AF: 0.644

Gnomad AMI AF: 0.330

Gnomad AMR AF: 0.294

Gnomad ASJ AF: 0.183

Gnomad EAS AF: 0.00521

Gnomad SAS AF: 0.183

Gnomad FIN AF: 0.235

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.228

Gnomad OTH AF: 0.321

GnomAD3 exomes AF: 0.236 AC: 58117 AN: 246654 Hom.: 8721 AF XY: 0.229 AC XY: 30662 AN XY: 133828

Gnomad AFR exome AF: 0.655

Gnomad AMR exome AF: 0.231

Gnomad ASJ exome AF: 0.191

Gnomad EAS exome AF: 0.00331

Gnomad SAS exome AF: 0.200

Gnomad FIN exome AF: 0.237

Gnomad NFE exome AF: 0.229

Gnomad OTH exome AF: 0.247

GnomAD4 exome AF: 0.228 AC: 331630 AN: 1452630 Hom.: 42897 Cov.: 29 AF XY: 0.226 AC XY: 163194 AN XY: 722888

Gnomad4 AFR exome AF: 0.667

Gnomad4 AMR exome AF: 0.239

Gnomad4 ASJ exome AF: 0.188

Gnomad4 EAS exome AF: 0.00212

Gnomad4 SAS exome AF: 0.203

Gnomad4 FIN exome AF: 0.239

Gnomad4 NFE exome AF: 0.224

Gnomad4 OTH exome AF: 0.241

GnomAD4 genome AF: 0.340 AC: 51700 AN: 151920 Hom.: 11653 Cov.: 31 AF XY: 0.335 AC XY: 24879 AN XY: 74254

Gnomad4 AFR AF: 0.644

Gnomad4 AMR AF: 0.294

Gnomad4 ASJ AF: 0.183

Gnomad4 EAS AF: 0.00522

Gnomad4 SAS AF: 0.183

Gnomad4 FIN AF: 0.235

Gnomad4 NFE AF: 0.228

Gnomad4 OTH AF: 0.319

Alfa AF: 0.240 Hom.: 9528

Bravo AF: 0.357

Asia WGS AF: 0.149 AC: 517 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Ser453Ser in exon 10 of CCDC39: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 37.4% (1391/3724) of African American chromosomes from a broad population by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS; dbSNP rs6769457). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 07, 2016	This 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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Primary ciliary dyskinesia 14 Benign:2

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
Cadd	Benign	5.8
Dann	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs6769457; hg19: chr3-180365956; COSMIC: COSV56496618;