Genetic Variant CCDC40:p.Ala369Ser (chr17-80050229-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_017950.4(CCDC40):c.1105G>T(p.Ala369Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,448,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A369T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CCDC40
NM_017950.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.617

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:

ENSG00000289689 (HGNC:):

ENSG00000289689 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1273801).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC40	NM_017950.4 link	c.1105G>T	p.Ala369Ser	missense_variant	Exon 7 of 20	ENST00000397545.9	NP_060420.2	Q4G0X9-1
CCDC40	NM_001243342.2 link	c.1105G>T	p.Ala369Ser	missense_variant	Exon 7 of 18		NP_001230271.1	Q4G0X9-2
CCDC40	NM_001330508.2 link	c.1105G>T	p.Ala369Ser	missense_variant	Exon 7 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.1105G>T	p.Ala369Ser	missense_variant	Exon 7 of 20	5	NM_017950.4	ENSP00000380679.4		Q4G0X9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.90e-7

AC:

AN:

1448704

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

720080

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33116

American (AMR)

AF:

0.00

AC:

AN:

42796

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25864

East Asian (EAS)

AF:

0.00

AC:

AN:

39072

South Asian (SAS)

AF:

0.00

AC:

AN:

84830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51664

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4318

European-Non Finnish (NFE)

AF:

9.03e-7

AC:

AN:

1107278

Other (OTH)

AF:

0.00

AC:

AN:

59766

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

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.63

CADD

Benign

3.1

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.087

.;T;.;.

Eigen

Benign

-0.87

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.73

T;T;T;T

M_CAP

Benign

0.021

MetaRNN

Benign

0.13

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;L;L;L

PhyloP100

-0.62

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.0

N;N;N;N

REVEL

Benign

0.025

Sift

Benign

0.042

D;D;T;T

Sift4G

Benign

0.75

T;T;T;T

Polyphen

0.36, 0.77

.;B;.;P

Vest4

0.21

MutPred

0.29

Gain of phosphorylation at A369 (P = 0.0369);Gain of phosphorylation at A369 (P = 0.0369);Gain of phosphorylation at A369 (P = 0.0369);Gain of phosphorylation at A369 (P = 0.0369);

MVP

0.081

MPC

0.18

ClinPred

0.13

GERP RS

-1.4

Varity_R

0.058

gMVP

0.091

Mutation Taster

=97/3

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over