rs111822347

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_017950.4(CCDC40):c.32C>G(p.Ser11Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000971 in 1,606,834 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00033 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000073 ( 0 hom. )

Consequence

CCDC40
NM_017950.4 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.79

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]

CCDC40 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.02681005).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CCDC40	NM_017950.4 linkuse as main transcript	c.32C>G	p.Ser11Cys	missense_variant, splice_region_variant	2/20	ENST00000397545.9
CCDC40	NM_001243342.2 linkuse as main transcript	c.32C>G	p.Ser11Cys	missense_variant, splice_region_variant	2/18
CCDC40	NM_001330508.2 linkuse as main transcript	c.32C>G	p.Ser11Cys	missense_variant, splice_region_variant	2/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC40	ENST00000397545.9 linkuse as main transcript	c.32C>G	p.Ser11Cys	missense_variant, splice_region_variant	2/20	5	NM_017950.4	P2	Q4G0X9-1

Frequencies

GnomAD3 genomes

AF:

0.000315

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00113

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000684

AC:

AN:

248536

Hom.:

AF XY:

0.0000445

AC XY:

AN XY:

134854

show subpopulations

Gnomad AFR exome

AF:

0.000793

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000266

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000729

AC:

106

AN:

1454514

Hom.:

Cov.:

AF XY:

0.0000732

AC XY:

AN XY:

723992

show subpopulations

Gnomad4 AFR exome

AF:

0.00153

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000465

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000190

Gnomad4 OTH exome

AF:

0.000349

GnomAD4 genome

AF:

0.000328

AC:

AN:

152320

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.00118

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000169

Hom.:

Bravo

AF:

0.000321

ESP6500AA

AF:

0.000817

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000745

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 12, 2024	The p.S11C variant (also known as c.32C>G), located in coding exon 2 of the CCDC40 gene, results from a C to G substitution at nucleotide position 32. The serine at codon 11 is replaced by cysteine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 19, 2022	This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 11 of the CCDC40 protein (p.Ser11Cys). This variant is present in population databases (rs111822347, gnomAD 0.1%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with CCDC40-related conditions. ClinVar contains an entry for this variant (Variation ID: 525443). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.35

Cadd

Benign

Dann

Uncertain

0.99

Eigen

Benign

0.17

Eigen_PC

Benign

0.080

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.55

T;T;T;T

M_CAP

Benign

0.037

MetaRNN

Benign

0.027

T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.69

N;N;N;N

MutationTaster

Benign

0.98

N;N;N;N

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.1

N;N;N;N

REVEL

Benign

0.11

Sift

Uncertain

0.0090

D;D;D;D

Sift4G

Uncertain

0.017

D;D;D;D

Polyphen

1.0, 1.0

.;D;.;D

Vest4

0.39

MVP

0.65

MPC

0.48

ClinPred

0.060

GERP RS

3.1

Varity_R

0.14

gMVP

0.12

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.

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