rs112738198

Positions:

Variant summary

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

The NM_181426.2(CCDC39):c.545C>G(p.Thr182Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0318 in 1,610,888 control chromosomes in the GnomAD database, including 971 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 73 hom., cov: 32)

Exomes 𝑓: 0.032 ( 898 hom. )

Consequence

CCDC39
NM_181426.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 5.82

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:

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=0.0033574104).

BP6

Variant 3-180659741-G-C is Benign according to our data. Variant chr3-180659741-G-C is described in ClinVar as [Benign]. Clinvar id is 162844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-180659741-G-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0251 (3828/152228) while in subpopulation NFE AF= 0.0391 (2660/67974). AF 95% confidence interval is 0.0379. There are 73 homozygotes in gnomad4. There are 1820 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 73 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC39	NM_181426.2 linkuse as main transcript	c.545C>G	p.Thr182Ser	missense_variant	5/20	ENST00000476379.6	NP_852091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC39	ENST00000476379.6 linkuse as main transcript	c.545C>G	p.Thr182Ser	missense_variant	5/20	2	NM_181426.2	ENSP00000417960	P2	Q9UFE4-1

Frequencies

GnomAD3 genomes

AF:

0.0252

AC:

3828

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00668

Gnomad AMI

AF:

0.128

Gnomad AMR

AF:

0.0221

Gnomad ASJ

AF:

0.00692

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.00476

Gnomad FIN

AF:

0.0331

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0391

Gnomad OTH

AF:

0.0177

GnomAD3 exomes

AF:

0.0241

AC:

5985

AN:

248098

Hom.:

AF XY:

0.0239

AC XY:

3214

AN XY:

134646

show subpopulations

Gnomad AFR exome

AF:

0.00530

Gnomad AMR exome

AF:

0.0152

Gnomad ASJ exome

AF:

0.00767

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00528

Gnomad FIN exome

AF:

0.0307

Gnomad NFE exome

AF:

0.0384

Gnomad OTH exome

AF:

0.0278

GnomAD4 exome

AF:

0.0325

AC:

47386

AN:

1458660

Hom.:

898

Cov.:

AF XY:

0.0320

AC XY:

23217

AN XY:

725682

show subpopulations

Gnomad4 AFR exome

AF:

0.00568

Gnomad4 AMR exome

AF:

0.0150

Gnomad4 ASJ exome

AF:

0.00858

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00583

Gnomad4 FIN exome

AF:

0.0299

Gnomad4 NFE exome

AF:

0.0384

Gnomad4 OTH exome

AF:

0.0256

GnomAD4 genome

AF:

0.0251

AC:

3828

AN:

152228

Hom.:

Cov.:

AF XY:

0.0244

AC XY:

1820

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.00666

Gnomad4 AMR

AF:

0.0221

Gnomad4 ASJ

AF:

0.00692

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.00476

Gnomad4 FIN

AF:

0.0331

Gnomad4 NFE

AF:

0.0391

Gnomad4 OTH

AF:

0.0175

Alfa

AF:

0.0310

Hom.:

Bravo

AF:

0.0235

TwinsUK

AF:

0.0388

AC:

144

ALSPAC

AF:

0.0381

AC:

147

ESP6500AA

AF:

0.00936

AC:

ESP6500EA

AF:

0.0323

AC:

263

ExAC

AF:

0.0245

AC:

2958

Asia WGS

AF:

0.00115

AC:

AN:

3476

EpiCase

AF:

0.0391

EpiControl

AF:

0.0321

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Thr182Ser in exon 5 of CCDC39: This variant is not expected to have clinical sig nificance because it has been identified in 3.2% (263/8154) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs112738198). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Primary ciliary dyskinesia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 30, 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. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Primary ciliary dyskinesia 14

Benign:1

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

-0.56

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.041

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.54

MetaRNN

Benign

0.0034

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

MutationTaster

Benign

0.96

D;D

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.11

Sift

Uncertain

0.022

Sift4G

Benign

0.18

Polyphen

0.98

Vest4

0.15

MutPred

0.14

Gain of glycosylation at T182 (P = 0.096);

MPC

0.14

ClinPred

0.036

GERP RS

4.0

Varity_R

0.15

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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