rs117419007

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_017950.4(CCDC40):​c.630C>T​(p.Ser210Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00592 in 1,613,620 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0048 ( 5 hom., cov: 33)
Exomes 𝑓: 0.0060 ( 41 hom. )

Consequence

CCDC40
NM_017950.4 synonymous

Scores

1
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 0.244
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 -14 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.69).
BP6
Variant 17-80047356-C-T is Benign according to our data. Variant chr17-80047356-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 197317.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=5, Uncertain_significance=1}.
BP7
Synonymous conserved (PhyloP=0.244 with no splicing effect.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00478 (728/152296) while in subpopulation NFE AF= 0.00566 (385/68018). AF 95% confidence interval is 0.00519. There are 5 homozygotes in gnomad4. There are 368 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CCDC40NM_017950.4 linkc.630C>T p.Ser210Ser synonymous_variant Exon 4 of 20 ENST00000397545.9 NP_060420.2 Q4G0X9-1
CCDC40NM_001243342.2 linkc.630C>T p.Ser210Ser synonymous_variant Exon 4 of 18 NP_001230271.1 Q4G0X9-2
CCDC40NM_001330508.2 linkc.630C>T p.Ser210Ser synonymous_variant Exon 4 of 11 NP_001317437.1 Q4G0X9-4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CCDC40ENST00000397545.9 linkc.630C>T p.Ser210Ser synonymous_variant Exon 4 of 20 5 NM_017950.4 ENSP00000380679.4 Q4G0X9-1

Frequencies

GnomAD3 genomes
AF:
0.00478
AC:
727
AN:
152178
Hom.:
5
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00106
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00347
Gnomad ASJ
AF:
0.00635
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00476
Gnomad FIN
AF:
0.0179
Gnomad MID
AF:
0.0127
Gnomad NFE
AF:
0.00564
Gnomad OTH
AF:
0.00335
GnomAD3 exomes
AF:
0.00598
AC:
1484
AN:
248064
Hom.:
8
AF XY:
0.00603
AC XY:
813
AN XY:
134846
show subpopulations
Gnomad AFR exome
AF:
0.000976
Gnomad AMR exome
AF:
0.00241
Gnomad ASJ exome
AF:
0.00628
Gnomad EAS exome
AF:
0.000111
Gnomad SAS exome
AF:
0.00550
Gnomad FIN exome
AF:
0.0219
Gnomad NFE exome
AF:
0.00582
Gnomad OTH exome
AF:
0.00564
GnomAD4 exome
AF:
0.00604
AC:
8821
AN:
1461324
Hom.:
41
Cov.:
33
AF XY:
0.00604
AC XY:
4388
AN XY:
726986
show subpopulations
Gnomad4 AFR exome
AF:
0.000896
Gnomad4 AMR exome
AF:
0.00298
Gnomad4 ASJ exome
AF:
0.00597
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00517
Gnomad4 FIN exome
AF:
0.0224
Gnomad4 NFE exome
AF:
0.00587
Gnomad4 OTH exome
AF:
0.00528
GnomAD4 genome
AF:
0.00478
AC:
728
AN:
152296
Hom.:
5
Cov.:
33
AF XY:
0.00494
AC XY:
368
AN XY:
74478
show subpopulations
Gnomad4 AFR
AF:
0.00106
Gnomad4 AMR
AF:
0.00346
Gnomad4 ASJ
AF:
0.00635
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00476
Gnomad4 FIN
AF:
0.0179
Gnomad4 NFE
AF:
0.00566
Gnomad4 OTH
AF:
0.00332
Alfa
AF:
0.00487
Hom.:
5
Bravo
AF:
0.00356
Asia WGS
AF:
0.00231
AC:
8
AN:
3478
EpiCase
AF:
0.00474
EpiControl
AF:
0.00540

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:6
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Benign:2
Feb 17, 2015
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Primary ciliary dyskinesia Benign:2
Jan 29, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 08, 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. -

not provided Benign:2
Nov 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

CCDC40: BP4, BP7, BS2 -

Nov 05, 2020
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Primary ciliary dyskinesia 15 Uncertain:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.69
CADD
Benign
5.9
DANN
Uncertain
0.98
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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: rs117419007; hg19: chr17-78021155; API