17-80087708-C-G

Position:

• chr17-80087708-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_017950.4(CCDC40):​c.2551C>G​(p.Arg851Gly) 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. 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. R851Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CCDC40 NM_017950.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.94

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29890987).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC40	NM_017950.4	c.2551C>G	p.Arg851Gly	missense_variant	15/20	ENST00000397545.9
CCDC40	NM_001243342.2	c.2551C>G	p.Arg851Gly	missense_variant	15/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC40	ENST00000397545.9	c.2551C>G	p.Arg851Gly	missense_variant	15/20	5	NM_017950.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	.;T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.87	D;T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	2.0	M;M
MutationTaster	Benign	0.67	D;D
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Benign	0.18
Sift	Benign	0.17	T;T
Sift4G	Uncertain	0.053	T;T
Polyphen		0.16	.;B
Vest4		0.29
MutPred		0.55		Loss of MoRF binding (P = 0.0109);Loss of MoRF binding (P = 0.0109);
MVP		0.46
MPC		0.33
ClinPred		0.22	T
GERP RS		3.7
Varity_R		0.16
gMVP		0.12

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

Other links and lift over

dbSNP: rs774273644; hg19: chr17-78061507;