rs387907091

Positions:

• chr17-80058649-C-G
• chr17-80058649-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_017950.4(CCDC40):​c.1315C>G​(p.Gln439Glu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CCDC40 NM_017950.4 missense, splice_region
• Scores: Splicing: ADA: 0.003462
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.52

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.75

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC40	NM_017950.4	c.1315C>G	p.Gln439Glu	missense_variant, splice_region_variant	8/20	ENST00000397545.9	NP_060420.2
CCDC40	NM_001243342.2	c.1315C>G	p.Gln439Glu	missense_variant, splice_region_variant	8/18		NP_001230271.1
CCDC40	NM_001330508.2	c.1315C>G	p.Gln439Glu	missense_variant, splice_region_variant	8/11		NP_001317437.1
LOC124904074	XR_007065931.1	n.1142G>C		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC40	ENST00000397545.9	c.1315C>G	p.Gln439Glu	missense_variant, splice_region_variant	8/20	5	NM_017950.4	ENSP00000380679.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.66	.;D;.;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D;D;D;T
M_CAP	Uncertain	0.089	D
MetaRNN	Uncertain	0.69	D;D;D;D
MetaSVM	Uncertain	-0.052	T
MutationAssessor	Pathogenic	3.0	M;M;M;M
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.8	D;D;D;D
REVEL	Uncertain	0.38
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Benign	0.22	T;T;D;D
Polyphen		1.0, 1.0	.;D;.;D
Vest4		0.84
MutPred		0.45		Loss of MoRF binding (P = 0.0622);Loss of MoRF binding (P = 0.0622);Loss of MoRF binding (P = 0.0622);Loss of MoRF binding (P = 0.0622);
MVP		0.41
MPC		0.74
ClinPred		0.95	D
GERP RS		4.1
Varity_R		0.50
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0035
dbscSNV1_RF	Benign	0.17
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

Other links and lift over

dbSNP: rs387907091; hg19: chr17-78032448;