rs79329972

chr3-180652189-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_181426.2(CCDC39):c.1008G>A(p.Lys336=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 1,528,792 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (50 hom.)
• Consequence: CCDC39 NM_181426.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.37

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 3-180652189-C-T is Benign according to our data. Variant chr3-180652189-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 262960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.37 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00272 (414/152114) while in subpopulation EAS AF= 0.0394 (204/5182). AF 95% confidence interval is 0.0349. There are 4 homozygotes in gnomad4. There are 252 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC39	NM_181426.2	c.1008G>A	p.Lys336=	synonymous_variant	8/20	ENST00000476379.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC39	ENST00000476379.6	c.1008G>A	p.Lys336=	synonymous_variant	8/20	2	NM_181426.2	P2

Frequencies

GnomAD3 genomes AF: 0.00273 AC: 415 AN: 151996 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.0393

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0110

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000971

Gnomad OTH AF: 0.000959

GnomAD3 exomes AF: 0.00419 AC: 612 AN: 146088 Hom.: 13 AF XY: 0.00387 AC XY: 297 AN XY: 76684

Gnomad AFR exome AF: 0.000259

Gnomad AMR exome AF: 0.000137

Gnomad ASJ exome AF: 0.00120

Gnomad EAS exome AF: 0.0367

Gnomad SAS exome AF: 0.000620

Gnomad FIN exome AF: 0.0110

Gnomad NFE exome AF: 0.000687

Gnomad OTH exome AF: 0.00193

GnomAD4 exome AF: 0.00200 AC: 2759 AN: 1376678 Hom.: 50 Cov.: 28 AF XY: 0.00198 AC XY: 1344 AN XY: 678014

Gnomad4 AFR exome AF: 0.0000327

Gnomad4 AMR exome AF: 0.000272

Gnomad4 ASJ exome AF: 0.00125

Gnomad4 EAS exome AF: 0.0440

Gnomad4 SAS exome AF: 0.000839

Gnomad4 FIN exome AF: 0.00910

Gnomad4 NFE exome AF: 0.000512

Gnomad4 OTH exome AF: 0.00219

GnomAD4 genome AF: 0.00272 AC: 414 AN: 152114 Hom.: 4 Cov.: 32 AF XY: 0.00339 AC XY: 252 AN XY: 74376

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.0394

Gnomad4 SAS AF: 0.00229

Gnomad4 FIN AF: 0.0110

Gnomad4 NFE AF: 0.000971

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00125 Hom.: 1

Bravo AF: 0.00215

Asia WGS AF: 0.0100 AC: 35 AN: 3470

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 26, 2019	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 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
BayesDel_noAF	Benign	-0.29
Cadd	Benign	6.5
Dann	Benign	0.67

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: rs79329972; hg19: chr3-180369977;