17-80036673-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_017950.4(CCDC40):c.11C>T(p.Pro4Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000336 in 1,459,926 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P4S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000037 ( 1 hom. )

Consequence

CCDC40
NM_017950.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.397

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

primary ciliary dyskinesia 15
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, Laboratory for Molecular Medicine
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autoimmune disease
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

CCDC40 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.059640735).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC40	NM_017950.4 link	c.11C>T	p.Pro4Leu	missense_variant	Exon 1 of 20	ENST00000397545.9	NP_060420.2	Q4G0X9-1
CCDC40	NM_001243342.2 link	c.11C>T	p.Pro4Leu	missense_variant	Exon 1 of 18		NP_001230271.1	Q4G0X9-2
CCDC40	NM_001330508.2 link	c.11C>T	p.Pro4Leu	missense_variant	Exon 1 of 11		NP_001317437.1	Q4G0X9-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC40	ENST00000397545.9 link	c.11C>T	p.Pro4Leu	missense_variant	Exon 1 of 20	5	NM_017950.4	ENSP00000380679.4		Q4G0X9-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151932

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000608

AC:

AN:

98676

AF XY:

0.0000710

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000467

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000367

AC:

AN:

1307994

Hom.:

Cov.:

AF XY:

0.0000451

AC XY:

AN XY:

642914

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27690

American (AMR)

AF:

0.00

AC:

AN:

26754

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22674

East Asian (EAS)

AF:

0.00

AC:

AN:

30160

South Asian (SAS)

AF:

0.000530

AC:

AN:

69764

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31878

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4774

European-Non Finnish (NFE)

AF:

0.00000961

AC:

AN:

1040324

Other (OTH)

AF:

0.0000185

AC:

AN:

53976

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151932

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74216

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41344

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.000208

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67958

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000388

AC:

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

Oct 15, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has not been reported in the literature in individuals with CCDC40-related disease. While this variant is present in population databases (rs776947186), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change replaces proline with leucine at codon 4 of the CCDC40 protein (p.Pro4Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. 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: "Benign"; 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. -

Sep 11, 2019

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.P4L variant (also known as c.11C>T), located in coding exon 1 of the CCDC40 gene, results from a C to T substitution at nucleotide position 11. The proline at codon 4 is replaced by leucine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species; however, leucine is the reference amino acid in other 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.098

.;T;.;.

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.73

T;T;T;T

M_CAP

Benign

0.053

MetaRNN

Benign

0.060

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

N;N;N;N

PhyloP100

-0.40

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-2.4

N;N;D;D

REVEL

Benign

0.047

Sift

Uncertain

0.0090

D;D;D;D

Sift4G

Uncertain

0.056

T;D;D;D

Polyphen

0.98, 1.0

.;D;.;D

Vest4

0.27

MutPred

0.22

Loss of loop (P = 0.0389);Loss of loop (P = 0.0389);Loss of loop (P = 0.0389);Loss of loop (P = 0.0389);

MVP

0.28

MPC

0.19

ClinPred

0.16

GERP RS

0.74

PromoterAI

-0.047

Neutral

(source)

Varity_R

0.086

gMVP

0.12

Mutation Taster

=88/12

polymorphism

(source)

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

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17-80036673-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over