rs11914833

chr3-180616931-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.2301G>A(p.Leu767=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0499 in 1,483,642 control chromosomes in the GnomAD database, including 3,162 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L767L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.092 (1063 hom., cov: 32)
  • Exomes 𝑓: 0.045 (2099 hom.)
• Consequence: CCDC39 NM_181426.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.742

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=-0.79).
• BP6: Variant 3-180616931-C-T is Benign according to our data. Variant chr3-180616931-C-T is described in ClinVar as [Benign]. Clinvar id is 162840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-180616931-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.742 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC39	NM_181426.2	c.2301G>A	p.Leu767=	synonymous_variant	17/20	ENST00000476379.6
TTC14	NM_001288582.2	c.1775-449C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC39	ENST00000476379.6	c.2301G>A	p.Leu767=	synonymous_variant	17/20	2	NM_181426.2	P2

Frequencies

GnomAD3 genomes AF: 0.0921 AC: 13990 AN: 151942 Hom.: 1051 Cov.: 32

Gnomad AFR AF: 0.212

Gnomad AMI AF: 0.146

Gnomad AMR AF: 0.0753

Gnomad ASJ AF: 0.0534

Gnomad EAS AF: 0.00288

Gnomad SAS AF: 0.0824

Gnomad FIN AF: 0.00728

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0454

Gnomad OTH AF: 0.0852

GnomAD3 exomes AF: 0.0556 AC: 11959 AN: 215174 Hom.: 618 AF XY: 0.0562 AC XY: 6533 AN XY: 116244

Gnomad AFR exome AF: 0.215

Gnomad AMR exome AF: 0.0441

Gnomad ASJ exome AF: 0.0555

Gnomad EAS exome AF: 0.00157

Gnomad SAS exome AF: 0.0869

Gnomad FIN exome AF: 0.00684

Gnomad NFE exome AF: 0.0459

Gnomad OTH exome AF: 0.0678

GnomAD4 exome AF: 0.0450 AC: 59959 AN: 1331582 Hom.: 2099 Cov.: 24 AF XY: 0.0464 AC XY: 30909 AN XY: 665944

Gnomad4 AFR exome AF: 0.211

Gnomad4 AMR exome AF: 0.0472

Gnomad4 ASJ exome AF: 0.0510

Gnomad4 EAS exome AF: 0.00101

Gnomad4 SAS exome AF: 0.0829

Gnomad4 FIN exome AF: 0.00714

Gnomad4 NFE exome AF: 0.0395

Gnomad4 OTH exome AF: 0.0574

GnomAD4 genome AF: 0.0923 AC: 14029 AN: 152060 Hom.: 1063 Cov.: 32 AF XY: 0.0890 AC XY: 6614 AN XY: 74336

Gnomad4 AFR AF: 0.212

Gnomad4 AMR AF: 0.0751

Gnomad4 ASJ AF: 0.0534

Gnomad4 EAS AF: 0.00289

Gnomad4 SAS AF: 0.0817

Gnomad4 FIN AF: 0.00728

Gnomad4 NFE AF: 0.0453

Gnomad4 OTH AF: 0.0862

Alfa AF: 0.0620 Hom.: 288

Bravo AF: 0.101

Asia WGS AF: 0.0730 AC: 252 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Leu767Leu 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 20.2% (724/3588) o f African American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs11914833). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 26, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 21, 2019

- -

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	-0.79
Cadd	Benign	2.0
Dann	Benign	0.53
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7

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

Other links and lift over

dbSNP: rs11914833; hg19: chr3-180334719;