17-80086022-T-G

Variant summary

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

The NM_017950.4(CCDC40):c.2255T>G(p.Leu752Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. L752P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CCDC40 NM_017950.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.68

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.833

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC40	NM_017950.4	c.2255T>G	p.Leu752Arg	missense_variant	14/20	ENST00000397545.9
CCDC40	NM_001243342.2	c.2255T>G	p.Leu752Arg	missense_variant	14/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC40	ENST00000397545.9	c.2255T>G	p.Leu752Arg	missense_variant	14/20	5	NM_017950.4	P2
CCDC40	ENST00000574799.5	n.1792T>G		non_coding_transcript_exon_variant	10/16	1
CCDC40	ENST00000374877.7	c.2255T>G	p.Leu752Arg	missense_variant	14/18	5		A2
CCDC40	ENST00000572253.5	n.882T>G		non_coding_transcript_exon_variant	3/6	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461778 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727186

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

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	0.14	D
BayesDel_noAF	Uncertain	-0.040
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.84	T;T
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Benign	-0.33	T
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.0	D;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0010	D;D
Sift4G	Benign	0.23	T;T
Polyphen		1.0	.;D
Vest4		0.82
MutPred		0.32		Gain of disorder (P = 0.0252);Gain of disorder (P = 0.0252);
MVP		0.71
MPC		0.85
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.78
gMVP		0.81

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: rs117203086; hg19: chr17-78059821;