rs183413880

chr3-180651495-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_181426.2(CCDC39):c.1073C>T(p.Thr358Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00495 in 1,539,912 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0033 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (26 hom.)
• Consequence: CCDC39 NM_181426.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 1.09

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009362876).
• BP6: Variant 3-180651495-G-A is Benign according to our data. Variant chr3-180651495-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 166806.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Benign=2, Uncertain_significance=1}. Variant chr3-180651495-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0033 (502/152048) while in subpopulation NFE AF= 0.00488 (332/67968). AF 95% confidence interval is 0.00445. There are 2 homozygotes in gnomad4. There are 238 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC39	NM_181426.2	c.1073C>T	p.Thr358Ile	missense_variant	9/20	ENST00000476379.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC39	ENST00000476379.6	c.1073C>T	p.Thr358Ile	missense_variant	9/20	2	NM_181426.2	P2

Frequencies

GnomAD3 genomes AF: 0.00330 AC: 502 AN: 151930 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000895

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00315

Gnomad ASJ AF: 0.0176

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.000284

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00488

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.00382 AC: 585 AN: 153056 Hom.: 6 AF XY: 0.00397 AC XY: 319 AN XY: 80256

Gnomad AFR exome AF: 0.00108

Gnomad AMR exome AF: 0.00241

Gnomad ASJ exome AF: 0.0184

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00207

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00471

Gnomad OTH exome AF: 0.00532

GnomAD4 exome AF: 0.00513 AC: 7125 AN: 1387864 Hom.: 26 Cov.: 28 AF XY: 0.00513 AC XY: 3514 AN XY: 684612

Gnomad4 AFR exome AF: 0.000873

Gnomad4 AMR exome AF: 0.00277

Gnomad4 ASJ exome AF: 0.0173

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00232

Gnomad4 FIN exome AF: 0.000471

Gnomad4 NFE exome AF: 0.00555

Gnomad4 OTH exome AF: 0.00617

GnomAD4 genome AF: 0.00330 AC: 502 AN: 152048 Hom.: 2 Cov.: 32 AF XY: 0.00320 AC XY: 238 AN XY: 74340

Gnomad4 AFR AF: 0.000892

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.0176

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.000284

Gnomad4 NFE AF: 0.00488

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00531 Hom.: 6

Bravo AF: 0.00352

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.000848 AC: 3

ESP6500EA AF: 0.00472 AC: 38

ExAC AF: 0.00157 AC: 170

Asia WGS AF: 0.000289 AC: 1 AN: 3474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 14, 2020	This variant is associated with the following publications: (PMID: 31213628) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	CCDC39: BP4, BS2 -
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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Primary ciliary dyskinesia 14 Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 07, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Sep 28, 2020	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 28, 2018	- -
Likely 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	Aug 05, 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	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	4.6
Dann	Benign	0.91
DEOGEN2	Benign	0.0087	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.0094	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.25
Sift	Benign	0.055	T
Sift4G	Benign	0.15	T
Polyphen		0.22	B
Vest4		0.22
MVP		0.73
MPC		0.072
ClinPred		0.0099	T
GERP RS		-4.4
Varity_R		0.036

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs183413880; hg19: chr3-180369283;