chr17-80086207-C-G

Position:

• chr17-80086207-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_017950.4(CCDC40):​c.2440C>G​(p.Arg814Gly) 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 pathogenic outcome for this variant. 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.27

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.932

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC40	NM_017950.4	c.2440C>G	p.Arg814Gly	missense_variant	14/20	ENST00000397545.9
CCDC40	NM_001243342.2	c.2440C>G	p.Arg814Gly	missense_variant	14/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC40	ENST00000397545.9	c.2440C>G	p.Arg814Gly	missense_variant	14/20	5	NM_017950.4	P2
CCDC40	ENST00000574799.5	n.1977C>G		non_coding_transcript_exon_variant	10/16	1
CCDC40	ENST00000374877.7	c.2440C>G	p.Arg814Gly	missense_variant	14/18	5		A2
CCDC40	ENST00000572253.5	n.1067C>G		non_coding_transcript_exon_variant	3/6	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.67	.;D
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.82	T;T
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Benign	-0.44	T
MutationAssessor	Pathogenic	2.9	M;M
MutationTaster	Benign	0.91	N;N
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-6.4	D;D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.042	D;T
Polyphen		0.99	.;D
Vest4		0.84
MutPred		0.58		Loss of MoRF binding (P = 0.0039);Loss of MoRF binding (P = 0.0039);
MVP		0.63
MPC		0.80
ClinPred		0.99	D
GERP RS		1.7
Varity_R		0.36
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs747233125; hg19: chr17-78060006;