rs115952495

chr3-180661985-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_181426.2(CCDC39):c.233G>A(p.Arg78His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00647 in 1,552,978 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R78C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0047 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0067 (55 hom.)
• Consequence: CCDC39 NM_181426.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.724

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=0.0032339096).
• BP6: Variant 3-180661985-C-T is Benign according to our data. Variant chr3-180661985-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 221189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00468 (713/152196) while in subpopulation SAS AF= 0.0183 (88/4820). AF 95% confidence interval is 0.0152. There are 5 homozygotes in gnomad4. There are 358 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC39	NM_181426.2	c.233G>A	p.Arg78His	missense_variant	3/20	ENST00000476379.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC39	ENST00000476379.6	c.233G>A	p.Arg78His	missense_variant	3/20	2	NM_181426.2	P2

Frequencies

GnomAD3 genomes AF: 0.00469 AC: 713 AN: 152078 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00126

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0182

Gnomad FIN AF: 0.00877

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00587

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00722 AC: 1159 AN: 160442 Hom.: 10 AF XY: 0.00804 AC XY: 679 AN XY: 84444

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.0185

Gnomad EAS exome AF: 0.000266

Gnomad SAS exome AF: 0.0173

Gnomad FIN exome AF: 0.00842

Gnomad NFE exome AF: 0.00636

Gnomad OTH exome AF: 0.00535

GnomAD4 exome AF: 0.00666 AC: 9329 AN: 1400782 Hom.: 55 Cov.: 31 AF XY: 0.00690 AC XY: 4769 AN XY: 691044

Gnomad4 AFR exome AF: 0.00113

Gnomad4 AMR exome AF: 0.00112

Gnomad4 ASJ exome AF: 0.0161

Gnomad4 EAS exome AF: 0.000111

Gnomad4 SAS exome AF: 0.0177

Gnomad4 FIN exome AF: 0.00820

Gnomad4 NFE exome AF: 0.00618

Gnomad4 OTH exome AF: 0.00613

GnomAD4 genome AF: 0.00468 AC: 713 AN: 152196 Hom.: 5 Cov.: 32 AF XY: 0.00481 AC XY: 358 AN XY: 74390

Gnomad4 AFR AF: 0.00125

Gnomad4 AMR AF: 0.000720

Gnomad4 ASJ AF: 0.0147

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.0183

Gnomad4 FIN AF: 0.00877

Gnomad4 NFE AF: 0.00587

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00597 Hom.: 3

Bravo AF: 0.00364

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.00138 AC: 5

ESP6500EA AF: 0.00738 AC: 60

ExAC AF: 0.00479 AC: 502

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 19, 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	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	CCDC39: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 06, 2020	This variant is associated with the following publications: (PMID: 31213628) -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Primary ciliary dyskinesia 14 Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	8.5
Dann	Benign	0.97
DEOGEN2	Benign	0.0040	T;.
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.59	T;.
MetaRNN	Benign	0.0032	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.23	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.12
Sift	Benign	0.42	T;T
Sift4G	Benign	0.68	T;.
Polyphen		0.0070	B;.
Vest4		0.21
MVP		0.65
MPC		0.062
ClinPred		0.0057	T
GERP RS		2.6
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: rs115952495; hg19: chr3-180379773; COSMIC: COSV99871174;