3-180616835-C-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.2397G>A(p.Val799=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.193 in 1,606,498 control chromosomes in the GnomAD database, including 31,673 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (2813 hom., cov: 32)
  • Exomes 𝑓: 0.19 (28860 hom.)
• Consequence: CCDC39 NM_181426.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.448

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]

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

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 3-180616835-C-T is Benign according to our data. Variant chr3-180616835-C-T is described in ClinVar as [Benign]. Clinvar id is 162839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-180616835-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.448 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.206 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC39	NM_181426.2	c.2397G>A	p.Val799=	synonymous_variant	17/20	ENST00000476379.6
TTC14	NM_001288582.2	c.1775-545C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC39	ENST00000476379.6	c.2397G>A	p.Val799=	synonymous_variant	17/20	2	NM_181426.2	P2

Frequencies

GnomAD3 genomes AF: 0.185 AC: 28153 AN: 151998 Hom.: 2810 Cov.: 32

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.184

Gnomad AMR AF: 0.199

Gnomad ASJ AF: 0.147

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.111

Gnomad FIN AF: 0.248

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.209

Gnomad OTH AF: 0.192

GnomAD3 exomes AF: 0.176 AC: 43280 AN: 246428 Hom.: 4229 AF XY: 0.174 AC XY: 23216 AN XY: 133752

Gnomad AFR exome AF: 0.155

Gnomad AMR exome AF: 0.181

Gnomad ASJ exome AF: 0.156

Gnomad EAS exome AF: 0.00145

Gnomad SAS exome AF: 0.119

Gnomad FIN exome AF: 0.248

Gnomad NFE exome AF: 0.207

Gnomad OTH exome AF: 0.188

GnomAD4 exome AF: 0.194 AC: 282625 AN: 1454382 Hom.: 28860 Cov.: 30 AF XY: 0.192 AC XY: 138607 AN XY: 723594

Gnomad4 AFR exome AF: 0.153

Gnomad4 AMR exome AF: 0.184

Gnomad4 ASJ exome AF: 0.153

Gnomad4 EAS exome AF: 0.00106

Gnomad4 SAS exome AF: 0.124

Gnomad4 FIN exome AF: 0.252

Gnomad4 NFE exome AF: 0.207

Gnomad4 OTH exome AF: 0.182

GnomAD4 genome AF: 0.185 AC: 28177 AN: 152116 Hom.: 2813 Cov.: 32 AF XY: 0.185 AC XY: 13778 AN XY: 74348

Gnomad4 AFR AF: 0.160

Gnomad4 AMR AF: 0.200

Gnomad4 ASJ AF: 0.147

Gnomad4 EAS AF: 0.00232

Gnomad4 SAS AF: 0.112

Gnomad4 FIN AF: 0.248

Gnomad4 NFE AF: 0.209

Gnomad4 OTH AF: 0.190

Alfa AF: 0.193 Hom.: 2020

Bravo AF: 0.179

Asia WGS AF: 0.0600 AC: 211 AN: 3476

EpiCase AF: 0.202

EpiControl AF: 0.198

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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Val799Val in exon 17 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 19.5% (1589/8130) of European American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs7612917). -

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	Feb 01, 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	-0.52
Cadd	Benign	2.5
Dann	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs7612917; hg19: chr3-180334623;