Genetic Variant CCDC39:c.1167+1261A>G (chr3-180650140-T-C) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_181426.2(CCDC39):c.1167+1261A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000466 in 152,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 32)

Consequence

CCDC39
NM_181426.2 intron

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: -2.13

Variant links:

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 links:

ENSG00000145075 (HGNC:):

ENSG00000145075 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 3-180650140-T-C is Pathogenic according to our data. Variant chr3-180650140-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 410378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC39	NM_181426.2 link	c.1167+1261A>G		intron_variant	Intron 9 of 19	ENST00000476379.6	NP_852091.1	Q9UFE4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC39	ENST00000476379.6 link	c.1167+1261A>G		intron_variant	Intron 9 of 19	2	NM_181426.2	ENSP00000417960.2		Q9UFE4-1

Frequencies

GnomAD3 genomes

AF:

0.000467

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00167

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.000466

AC:

AN:

152296

Hom.:

Cov.:

AF XY:

0.000457

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00166

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000427

Hom.:

Bravo

AF:

0.000442

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Pathogenic:3

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 9 of the CCDC39 gene. It does not directly change the encoded amino acid sequence of the CCDC39 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs577069249, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with primary ciliary dyskinesia (PMID: 21131972; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 410378). Studies have shown that this variant results in activation of a pseudo-exon in intron 9, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 21131972). For these reasons, this variant has been classified as Pathogenic. -

Aug 01, 2018

Yale Center for Mendelian Genomics, Yale University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 07, 2018

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary ciliary dyskinesia 14

Pathogenic:2

Mar 06, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CCDC39 c.1167+1261A>G is located at a position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00061 in 31404 control chromosomes. c.1167+1261A>G has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Primary ciliary dyskinesia (e.g. Mani_2019, Davis_2019, Blanchon_2012, Alsamri_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34768622, 22693285, 30067075, 31469207). ClinVar contains an entry for this variant (Variation ID: 410378). Based on the evidence outlined above, the variant was classified as pathogenic. -

Apr 12, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:1

Aug 16, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate this variant results in activation of a pseudo-exon in intron 9 and is predicted to lead to p.(Glu390Serfs*6) (Merveille et al., 2011); This variant is associated with the following publications: (PMID: 21131972, 35051411, 31469207, 30067075, 22693285, 34768622) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

DANN

Benign

0.21

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.82

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.82

Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over