3-180660614-G-C

Variant names:

• chr3-180660614-G-C
• rs57838737
• NM_181426.2:c.472C>G

Variant summary

Our verdict is Benign. The variant received -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L158L) has been classified as Likely 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
• Publications: 3 publications found

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]

CCDC39 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 14

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000145075 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 226485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181426.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC39	NM_181426.2	MANE Select	c.472C>G	p.Leu158Val	missense	Exon 4 of 20	NP_852091.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC39	ENST00000476379.6	TSL:2 MANE Select	c.472C>G	p.Leu158Val	missense	Exon 4 of 20	ENSP00000417960.2
	CCDC39	ENST00000651046.1		c.472C>G	p.Leu158Val	missense	Exon 4 of 19	ENSP00000499175.1
	CCDC39	ENST00000650641.1		n.551C>G		non_coding_transcript_exon	Exon 4 of 16

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

GnomAD2 exomes AF: 0.00963 AC: 2228 AN: 231418 AF XY: 0.00754

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 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

African (AFR) AF: 0.139 AC: 4618 AN: 33290

American (AMR) AF: 0.00647 AC: 279 AN: 43152

Ashkenazi Jewish (ASJ) AF: 0.00233 AC: 60 AN: 25788

East Asian (EAS) AF: 0.00 AC: 0 AN: 39512

South Asian (SAS) AF: 0.000273 AC: 23 AN: 84104

European-Finnish (FIN) AF: 0.0000379 AC: 2 AN: 52820

Middle Eastern (MID) AF: 0.00765 AC: 44 AN: 5754

European-Non Finnish (NFE) AF: 0.000391 AC: 432 AN: 1104920

Other (OTH) AF: 0.00877 AC: 526 AN: 59960

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

African (AFR) AF: 0.131 AC: 5442 AN: 41500

American (AMR) AF: 0.0154 AC: 235 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000604 AC: 41 AN: 67936

Other (OTH) AF: 0.0308 AC: 65 AN: 2112

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

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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).

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Primary ciliary dyskinesia Benign:2

Jul 08, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 08, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Primary ciliary dyskinesia 14 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

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
PhyloP100		-0.43
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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs57838737; hg19: chr3-180378402;