17-80058885-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_017950.4(CCDC40):​c.1345C>G​(p.Arg449Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

CCDC40
NM_017950.4 missense

Scores

6
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0210
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.28720948).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CCDC40NM_017950.4 linkc.1345C>G p.Arg449Gly missense_variant 9/20 ENST00000397545.9 NP_060420.2 Q4G0X9-1
CCDC40NM_001243342.2 linkc.1345C>G p.Arg449Gly missense_variant 9/18 NP_001230271.1 Q4G0X9-2
CCDC40NM_001330508.2 linkc.1345C>G p.Arg449Gly missense_variant 9/11 NP_001317437.1 Q4G0X9-4
LOC124904074XR_007065931.1 linkn.906G>C non_coding_transcript_exon_variant 2/2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CCDC40ENST00000397545.9 linkc.1345C>G p.Arg449Gly missense_variant 9/205 NM_017950.4 ENSP00000380679.4 Q4G0X9-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 27, 2017In 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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals with CCDC40-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glycine at codon 449 of the CCDC40 protein (p.Arg449Gly). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and glycine. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.22
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Benign
-0.43
CADD
Benign
12
DANN
Benign
0.93
DEOGEN2
Uncertain
0.51
.;D;.
Eigen
Benign
-0.94
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.032
N
LIST_S2
Benign
0.77
T;T;T
M_CAP
Uncertain
0.10
D
MetaRNN
Benign
0.29
T;T;T
MetaSVM
Benign
-0.85
T
MutationAssessor
Uncertain
2.5
M;M;M
PrimateAI
Benign
0.22
T
PROVEAN
Uncertain
-4.2
D;D;D
REVEL
Benign
0.15
Sift
Uncertain
0.013
D;D;D
Sift4G
Uncertain
0.0080
D;T;D
Polyphen
0.73
.;P;.
Vest4
0.39
MutPred
0.26
Loss of catalytic residue at R449 (P = 0.0507);Loss of catalytic residue at R449 (P = 0.0507);Loss of catalytic residue at R449 (P = 0.0507);
MVP
0.24
MPC
0.51
ClinPred
0.56
D
GERP RS
-9.0
Varity_R
0.12
gMVP
0.15

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: rs387907093; hg19: chr17-78032684; API