rs57838737

Positions:

• chr3-180660614-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_181426.2(CCDC39):​c.472C>G​(p.Leu158Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00736 in 1,601,418 control chromosomes in the GnomAD database, including 733 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.038 (393 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (340 hom.)
• Consequence: CCDC39 NM_181426.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.430

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013329685).
• BP6: Variant 3-180660614-G-C is Benign according to our data. Variant chr3-180660614-G-C is described in ClinVar as [Benign]. Clinvar id is 226485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-180660614-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC39	NM_181426.2	c.472C>G	p.Leu158Val	missense_variant	4/20	ENST00000476379.6	NP_852091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC39	ENST00000476379.6	c.472C>G	p.Leu158Val	missense_variant	4/20	2	NM_181426.2	ENSP00000417960	P2

Frequencies

GnomAD3 genomes AF: 0.0381 AC: 5785 AN: 152000 Hom.: 391 Cov.: 32

Gnomad AFR AF: 0.131

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0155

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.0311

GnomAD3 exomes AF: 0.00963 AC: 2228 AN: 231418 Hom.: 123 AF XY: 0.00754 AC XY: 940 AN XY: 124746

Gnomad AFR exome AF: 0.137

Gnomad AMR exome AF: 0.00523

Gnomad ASJ exome AF: 0.00270

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000354

Gnomad FIN exome AF: 0.0000961

Gnomad NFE exome AF: 0.000523

Gnomad OTH exome AF: 0.00506

GnomAD4 exome AF: 0.00413 AC: 5984 AN: 1449300 Hom.: 340 Cov.: 30 AF XY: 0.00362 AC XY: 2608 AN XY: 719576

Gnomad4 AFR exome AF: 0.139

Gnomad4 AMR exome AF: 0.00647

Gnomad4 ASJ exome AF: 0.00233

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000273

Gnomad4 FIN exome AF: 0.0000379

Gnomad4 NFE exome AF: 0.000391

Gnomad4 OTH exome AF: 0.00877

GnomAD4 genome AF: 0.0381 AC: 5798 AN: 152118 Hom.: 393 Cov.: 32 AF XY: 0.0366 AC XY: 2721 AN XY: 74372

Gnomad4 AFR AF: 0.131

Gnomad4 AMR AF: 0.0154

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000604

Gnomad4 OTH AF: 0.0308

Alfa AF: 0.0110 Hom.: 36

Bravo AF: 0.0439

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.130 AC: 480

ESP6500EA AF: 0.00110 AC: 9

ExAC AF: 0.0117 AC: 1406

Asia WGS AF: 0.00751 AC: 26 AN: 3478

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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Leu158Val in exon 4 of CCDC39: This variant is not expected to have clinical sig nificance because it has been identified in 13.0% (480/3692) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs57838737). -
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 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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 08, 2020	- -

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
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	6.3
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0039	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.067
Sift	Benign	0.11	T
Sift4G	Benign	0.079	T
Polyphen		0.045	B
Vest4		0.074
MPC		0.054
ClinPred		0.0037	T
GERP RS		0.80
Varity_R		0.039

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: rs57838737; hg19: chr3-180378402;