chr3-180647245-TG-T

Position:

chr3-180647245-TG-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_181426.2(CCDC39):c.1363-3delC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000843 in 1,558,374 control chromosomes in the GnomAD database, including 3 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00073 ( 3 hom. )

Consequence

CCDC39
NM_181426.2 splice_region, intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 3.55

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:

CCDC39 (HGNC:):

CCDC39 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP6

Variant 3-180647245-TG-T is Benign according to our data. Variant chr3-180647245-TG-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 242168.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2}. Variant chr3-180647245-TG-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00193 (288/149096) while in subpopulation AMR AF= 0.00555 (82/14764). AF 95% confidence interval is 0.00458. There are 0 homozygotes in gnomad4. There are 156 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC39	NM_181426.2 linkuse as main transcript	c.1363-3delC		splice_region_variant, intron_variant		ENST00000476379.6	NP_852091.1	Q9UFE4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC39	ENST00000476379.6 linkuse as main transcript	c.1363-3delC		splice_region_variant, intron_variant		2	NM_181426.2	ENSP00000417960.2		Q9UFE4-1

Frequencies

GnomAD3 genomes

AF:

0.00195

AC:

290

AN:

148984

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00364

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00556

Gnomad ASJ

AF:

0.000292

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000211

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0196

Gnomad NFE

AF:

0.000614

Gnomad OTH

AF:

0.00493

GnomAD3 exomes

AF:

0.00124

AC:

215

AN:

173520

Hom.:

AF XY:

0.00123

AC XY:

116

AN XY:

94036

show subpopulations

Gnomad AFR exome

AF:

0.00383

Gnomad AMR exome

AF:

0.00455

Gnomad ASJ exome

AF:

0.000530

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000477

Gnomad FIN exome

AF:

0.000113

Gnomad NFE exome

AF:

0.000829

Gnomad OTH exome

AF:

0.00211

GnomAD4 exome

AF:

0.000727

AC:

1025

AN:

1409278

Hom.:

Cov.:

AF XY:

0.000753

AC XY:

526

AN XY:

698472

show subpopulations

Gnomad4 AFR exome

AF:

0.00447

Gnomad4 AMR exome

AF:

0.00394

Gnomad4 ASJ exome

AF:

0.000573

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000648

Gnomad4 FIN exome

AF:

0.0000392

Gnomad4 NFE exome

AF:

0.000534

Gnomad4 OTH exome

AF:

0.00204

GnomAD4 genome

AF:

0.00193

AC:

288

AN:

149096

Hom.:

Cov.:

AF XY:

0.00215

AC XY:

156

AN XY:

72722

show subpopulations

Gnomad4 AFR

AF:

0.00359

Gnomad4 AMR

AF:

0.00555

Gnomad4 ASJ

AF:

0.000292

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000212

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000614

Gnomad4 OTH

AF:

0.00487

Alfa

AF:

0.000656

Hom.:

Bravo

AF:

0.00253

Asia WGS

AF:

0.000869

AC:

AN:

3468

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 28, 2019	In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21131972, 22693285) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	CCDC39: BP4, BS2 -

Primary ciliary dyskinesia

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 06, 2017	This alteration is classified as likely 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. -

Primary ciliary dyskinesia 14

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Mar 04, 2021

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 14, 2016

c.1363-3delC: This variant is not expected to have clinical significance because it has been identified in 0.35% (17/4804) of Latino chromosomes and 0.34% (22/6 500) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://ex ac.broadinstitute.org; dbSNP rs551191744). -

CCDC39-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 16, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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

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