rs74000351

Variant summary

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

The NM_017950.4(CCDC40):​c.504G>A​(p.Pro168=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00518 in 1,613,952 control chromosomes in the GnomAD database, including 309 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.026 ( 176 hom., cov: 32)
Exomes 𝑓: 0.0030 ( 133 hom. )

Consequence

CCDC40
NM_017950.4 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -2.97
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=-0.99).
BP6
Variant 17-80040222-G-A is Benign according to our data. Variant chr17-80040222-G-A is described in ClinVar as [Benign]. Clinvar id is 226494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-2.97 with no splicing effect.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0844 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CCDC40NM_017950.4 linkuse as main transcriptc.504G>A p.Pro168= synonymous_variant 3/20 ENST00000397545.9 NP_060420.2
CCDC40NM_001243342.2 linkuse as main transcriptc.504G>A p.Pro168= synonymous_variant 3/18 NP_001230271.1
CCDC40NM_001330508.2 linkuse as main transcriptc.504G>A p.Pro168= synonymous_variant 3/11 NP_001317437.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CCDC40ENST00000397545.9 linkuse as main transcriptc.504G>A p.Pro168= synonymous_variant 3/205 NM_017950.4 ENSP00000380679 P2Q4G0X9-1

Frequencies

GnomAD3 genomes
AF:
0.0256
AC:
3903
AN:
152174
Hom.:
176
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0867
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0119
Gnomad ASJ
AF:
0.00979
Gnomad EAS
AF:
0.00250
Gnomad SAS
AF:
0.000827
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.000559
Gnomad OTH
AF:
0.0182
GnomAD3 exomes
AF:
0.00735
AC:
1824
AN:
248174
Hom.:
64
AF XY:
0.00580
AC XY:
782
AN XY:
134910
show subpopulations
Gnomad AFR exome
AF:
0.0921
Gnomad AMR exome
AF:
0.00455
Gnomad ASJ exome
AF:
0.00858
Gnomad EAS exome
AF:
0.00312
Gnomad SAS exome
AF:
0.000425
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000606
Gnomad OTH exome
AF:
0.00464
GnomAD4 exome
AF:
0.00304
AC:
4440
AN:
1461660
Hom.:
133
Cov.:
33
AF XY:
0.00274
AC XY:
1990
AN XY:
727134
show subpopulations
Gnomad4 AFR exome
AF:
0.0892
Gnomad4 AMR exome
AF:
0.00544
Gnomad4 ASJ exome
AF:
0.00750
Gnomad4 EAS exome
AF:
0.00169
Gnomad4 SAS exome
AF:
0.000661
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000339
Gnomad4 OTH exome
AF:
0.00697
GnomAD4 genome
AF:
0.0257
AC:
3915
AN:
152292
Hom.:
176
Cov.:
32
AF XY:
0.0243
AC XY:
1807
AN XY:
74474
show subpopulations
Gnomad4 AFR
AF:
0.0868
Gnomad4 AMR
AF:
0.0118
Gnomad4 ASJ
AF:
0.00979
Gnomad4 EAS
AF:
0.00251
Gnomad4 SAS
AF:
0.000828
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000559
Gnomad4 OTH
AF:
0.0180
Alfa
AF:
0.00850
Hom.:
25
Bravo
AF:
0.0303
Asia WGS
AF:
0.0110
AC:
39
AN:
3478
EpiCase
AF:
0.000981
EpiControl
AF:
0.000830

ClinVar

Significance: 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 submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineFeb 21, 2013Pro168Pro in exon 3 of CCDC40: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 8.5% (336/3946) of African American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs74000351). -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Primary ciliary dyskinesia Benign:2
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Benign, criteria provided, single submitterclinical testingAmbry GeneticsOct 25, 2016This 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 submitterclinical testingGeneDxJul 05, 2018- -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Primary ciliary dyskinesia 15 Benign:2
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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. -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 29, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.99
CADD
Benign
1.4
DANN
Benign
0.51

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: rs74000351; hg19: chr17-78014021; COSMIC: COSV53899874; COSMIC: COSV53899874; API