17-80099763-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_017950.4(CCDC40):​c.3417A>G​(p.Pro1139Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.458 in 1,612,434 control chromosomes in the GnomAD database, including 171,762 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.49 ( 18977 hom., cov: 31)
Exomes 𝑓: 0.45 ( 152785 hom. )

Consequence

CCDC40
NM_017950.4 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -1.08
Variant links:
Genes affected
CCDC40 (HGNC:26090): (coiled-coil domain 40 molecular ruler complex subunit) This gene encodes a protein that is necessary for motile cilia function. It functions in correct left-right axis formation by regulating the assembly of the inner dynein arm and the dynein regulatory complexes, which control ciliary beat. Mutations in this gene cause ciliary dyskinesia type 15, a disorder due to defects in cilia motility. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.9).
BP6
Variant 17-80099763-A-G is Benign according to our data. Variant chr17-80099763-A-G is described in ClinVar as [Benign]. Clinvar id is 178712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80099763-A-G is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-1.09 with no splicing effect.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.599 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CCDC40NM_017950.4 linkc.3417A>G p.Pro1139Pro synonymous_variant Exon 20 of 20 ENST00000397545.9 NP_060420.2 Q4G0X9-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CCDC40ENST00000397545.9 linkc.3417A>G p.Pro1139Pro synonymous_variant Exon 20 of 20 5 NM_017950.4 ENSP00000380679.4 Q4G0X9-1
CCDC40ENST00000574799.5 linkn.2954A>G non_coding_transcript_exon_variant Exon 16 of 16 1

Frequencies

GnomAD3 genomes
AF:
0.492
AC:
74666
AN:
151786
Hom.:
18954
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.605
Gnomad AMI
AF:
0.437
Gnomad AMR
AF:
0.332
Gnomad ASJ
AF:
0.486
Gnomad EAS
AF:
0.425
Gnomad SAS
AF:
0.511
Gnomad FIN
AF:
0.542
Gnomad MID
AF:
0.596
Gnomad NFE
AF:
0.457
Gnomad OTH
AF:
0.466
GnomAD3 exomes
AF:
0.451
AC:
111378
AN:
247100
Hom.:
26325
AF XY:
0.461
AC XY:
61985
AN XY:
134524
show subpopulations
Gnomad AFR exome
AF:
0.610
Gnomad AMR exome
AF:
0.237
Gnomad ASJ exome
AF:
0.499
Gnomad EAS exome
AF:
0.410
Gnomad SAS exome
AF:
0.521
Gnomad FIN exome
AF:
0.536
Gnomad NFE exome
AF:
0.460
Gnomad OTH exome
AF:
0.475
GnomAD4 exome
AF:
0.454
AC:
662967
AN:
1460530
Hom.:
152785
Cov.:
50
AF XY:
0.457
AC XY:
331983
AN XY:
726564
show subpopulations
Gnomad4 AFR exome
AF:
0.615
Gnomad4 AMR exome
AF:
0.253
Gnomad4 ASJ exome
AF:
0.500
Gnomad4 EAS exome
AF:
0.454
Gnomad4 SAS exome
AF:
0.513
Gnomad4 FIN exome
AF:
0.542
Gnomad4 NFE exome
AF:
0.446
Gnomad4 OTH exome
AF:
0.468
GnomAD4 genome
AF:
0.492
AC:
74734
AN:
151904
Hom.:
18977
Cov.:
31
AF XY:
0.491
AC XY:
36484
AN XY:
74242
show subpopulations
Gnomad4 AFR
AF:
0.605
Gnomad4 AMR
AF:
0.331
Gnomad4 ASJ
AF:
0.486
Gnomad4 EAS
AF:
0.425
Gnomad4 SAS
AF:
0.511
Gnomad4 FIN
AF:
0.542
Gnomad4 NFE
AF:
0.457
Gnomad4 OTH
AF:
0.469
Alfa
AF:
0.450
Hom.:
22871
Bravo
AF:
0.479
EpiCase
AF:
0.454
EpiControl
AF:
0.453

ClinVar

Significance: Benign
Submissions summary: Benign:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:4
-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 21, 2013
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Pro1139Pro in exon 20 of CCDC40: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 44.7% (3724/8334) of European American chromosomes from a broad population by the NHLBI Exome Seq uencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2304854). -

May 07, 2014
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Primary ciliary dyskinesia Benign:3
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 07, 2016
Ambry Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Primary ciliary dyskinesia 15 Benign:3
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Jul 14, 2021
Genome-Nilou Lab
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not provided Benign:2
-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Jul 05, 2018
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Glycogen storage disease, type II Benign:1
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.90
CADD
Benign
0.060
DANN
Benign
0.34

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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.

Other links and lift over

dbSNP: rs2304854; hg19: chr17-78073562; COSMIC: COSV56409368; COSMIC: COSV56409368; API