rs2338436

Positions:

• chr3-180648279-T-C

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.1248A>G​(p.Glu416=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0581 in 1,612,916 control chromosomes in the GnomAD database, including 7,512 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (3205 hom., cov: 32)
  • Exomes 𝑓: 0.050 (4307 hom.)
• Consequence: CCDC39 NM_181426.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.566

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=-0.56).
• BP6: Variant 3-180648279-T-C is Benign according to our data. Variant chr3-180648279-T-C is described in ClinVar as [Benign]. Clinvar id is 162843.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-180648279-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.566 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.376 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC39	NM_181426.2	c.1248A>G	p.Glu416=	synonymous_variant	10/20	ENST00000476379.6	NP_852091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC39	ENST00000476379.6	c.1248A>G	p.Glu416=	synonymous_variant	10/20	2	NM_181426.2	ENSP00000417960	P2

Frequencies

GnomAD3 genomes AF: 0.137 AC: 20816 AN: 152058 Hom.: 3197 Cov.: 32

Gnomad AFR AF: 0.381

Gnomad AMI AF: 0.125

Gnomad AMR AF: 0.0845

Gnomad ASJ AF: 0.0354

Gnomad EAS AF: 0.00250

Gnomad SAS AF: 0.0767

Gnomad FIN AF: 0.00715

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0415

Gnomad OTH AF: 0.118

GnomAD3 exomes AF: 0.0627 AC: 15603 AN: 248748 Hom.: 1491 AF XY: 0.0602 AC XY: 8120 AN XY: 134946

Gnomad AFR exome AF: 0.393

Gnomad AMR exome AF: 0.0452

Gnomad ASJ exome AF: 0.0370

Gnomad EAS exome AF: 0.00189

Gnomad SAS exome AF: 0.0796

Gnomad FIN exome AF: 0.00655

Gnomad NFE exome AF: 0.0408

Gnomad OTH exome AF: 0.0632

GnomAD4 exome AF: 0.0499 AC: 72845 AN: 1460740 Hom.: 4307 Cov.: 31 AF XY: 0.0500 AC XY: 36308 AN XY: 726636

Gnomad4 AFR exome AF: 0.400

Gnomad4 AMR exome AF: 0.0505

Gnomad4 ASJ exome AF: 0.0355

Gnomad4 EAS exome AF: 0.00106

Gnomad4 SAS exome AF: 0.0795

Gnomad4 FIN exome AF: 0.00710

Gnomad4 NFE exome AF: 0.0401

Gnomad4 OTH exome AF: 0.0656

GnomAD4 genome AF: 0.137 AC: 20844 AN: 152176 Hom.: 3205 Cov.: 32 AF XY: 0.132 AC XY: 9831 AN XY: 74420

Gnomad4 AFR AF: 0.381

Gnomad4 AMR AF: 0.0843

Gnomad4 ASJ AF: 0.0354

Gnomad4 EAS AF: 0.00251

Gnomad4 SAS AF: 0.0761

Gnomad4 FIN AF: 0.00715

Gnomad4 NFE AF: 0.0414

Gnomad4 OTH AF: 0.116

Alfa AF: 0.0708 Hom.: 1198

Bravo AF: 0.154

Asia WGS AF: 0.0680 AC: 238 AN: 3478

EpiCase AF: 0.0488

EpiControl AF: 0.0506

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Glu416Glu 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 37.7% (1380/3662) of African American chromosomes from a broad population by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2338436). -

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 08, 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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 21, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Primary ciliary dyskinesia 14 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	2.4
DANN	Benign	0.66

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: rs2338436; hg19: chr3-180366067; COSMIC: COSV56486370;