3-180616670-C-T

Position:

chr3-180616670-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_181426.2(CCDC39):c.2432G>A(p.Arg811His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00499 in 1,590,776 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts 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. R811C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0051 ( 9 hom., cov: 32)

Exomes 𝑓: 0.0050 ( 68 hom. )

Consequence

CCDC39
NM_181426.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 3.28

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:

TTC14 (HGNC:24697): (tetratricopeptide repeat domain 14) Predicted to enable nucleic acid binding activity. [provided by Alliance of Genome Resources, Apr 2022]

TTC14 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005194932).

BP6

Variant 3-180616670-C-T is Benign according to our data. Variant chr3-180616670-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 162838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-180616670-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00515 (783/152128) while in subpopulation EAS AF= 0.0512 (265/5174). AF 95% confidence interval is 0.0462. There are 9 homozygotes in gnomad4. There are 404 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC39	NM_181426.2 linkuse as main transcript	c.2432G>A	p.Arg811His	missense_variant	18/20	ENST00000476379.6
TTC14	NM_001288582.2 linkuse as main transcript	c.1775-710C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC39	ENST00000476379.6 linkuse as main transcript	c.2432G>A	p.Arg811His	missense_variant	18/20	2	NM_181426.2	P2	Q9UFE4-1

Frequencies

GnomAD3 genomes

AF:

0.00515

AC:

783

AN:

152010

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00176

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00768

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.0511

Gnomad SAS

AF:

0.00684

Gnomad FIN

AF:

0.000567

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00376

Gnomad OTH

AF:

0.00479

GnomAD3 exomes

AF:

0.00812

AC:

1741

AN:

214414

Hom.:

AF XY:

0.00803

AC XY:

929

AN XY:

115640

show subpopulations

Gnomad AFR exome

AF:

0.00144

Gnomad AMR exome

AF:

0.00560

Gnomad ASJ exome

AF:

0.00676

Gnomad EAS exome

AF:

0.0562

Gnomad SAS exome

AF:

0.00695

Gnomad FIN exome

AF:

0.000603

Gnomad NFE exome

AF:

0.00379

Gnomad OTH exome

AF:

0.00800

GnomAD4 exome

AF:

0.00497

AC:

7153

AN:

1438648

Hom.:

Cov.:

AF XY:

0.00508

AC XY:

3626

AN XY:

713644

show subpopulations

Gnomad4 AFR exome

AF:

0.00160

Gnomad4 AMR exome

AF:

0.00572

Gnomad4 ASJ exome

AF:

0.00687

Gnomad4 EAS exome

AF:

0.0440

Gnomad4 SAS exome

AF:

0.00677

Gnomad4 FIN exome

AF:

0.000386

Gnomad4 NFE exome

AF:

0.00349

Gnomad4 OTH exome

AF:

0.00747

GnomAD4 genome

AF:

0.00515

AC:

783

AN:

152128

Hom.:

Cov.:

AF XY:

0.00543

AC XY:

404

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.00176

Gnomad4 AMR

AF:

0.00767

Gnomad4 ASJ

AF:

0.00634

Gnomad4 EAS

AF:

0.0512

Gnomad4 SAS

AF:

0.00684

Gnomad4 FIN

AF:

0.000567

Gnomad4 NFE

AF:

0.00377

Gnomad4 OTH

AF:

0.00474

Alfa

AF:

0.00611

Hom.:

Bravo

AF:

0.00602

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00467

AC:

ESP6500AA

AF:

0.00164

AC:

ESP6500EA

AF:

0.00405

AC:

ExAC

AF:

0.00709

AC:

852

Asia WGS

AF:

0.0200

AC:

AN:

3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Arg811His in exon 18 of CCDC39: This variant is not expected to have clinical si gnificance because it has been identified in 6.2% (12/194) of Han Chinese chromo somes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.n ih.gov/projects/SNP; dbSNP rs61733583). -

Primary ciliary dyskinesia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 19, 2018	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 provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -

Primary ciliary dyskinesia 14

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 17, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.15

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.042

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.82

MetaRNN

Benign

0.0052

MetaSVM

Benign

-0.38

MutationAssessor

Uncertain

2.6

MutationTaster

Benign

0.99

D;D;D

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-3.1

REVEL

Uncertain

0.39

Sift

Uncertain

0.0050

Sift4G

Benign

0.064

Polyphen

0.99

Vest4

0.43

MVP

0.80

MPC

0.32

ClinPred

0.023

GERP RS

5.1

Varity_R

0.15

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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