17-80058885-C-T

Position:

• chr17-80058885-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_017950.4(CCDC40):​c.1345C>T​(p.Arg449*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: CCDC40 NM_017950.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.0210

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-80058885-C-T is Pathogenic according to our data. Variant chr17-80058885-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 31072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC40	NM_017950.4	c.1345C>T	p.Arg449*	stop_gained	9/20	ENST00000397545.9	NP_060420.2
CCDC40	NM_001243342.2	c.1345C>T	p.Arg449*	stop_gained	9/18		NP_001230271.1
CCDC40	NM_001330508.2	c.1345C>T	p.Arg449*	stop_gained	9/11		NP_001317437.1
LOC124904074	XR_007065931.1	n.906G>A		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC40	ENST00000397545.9	c.1345C>T	p.Arg449*	stop_gained	9/20	5	NM_017950.4	ENSP00000380679.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461872 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727240

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: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000521 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia 15 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 28, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Oct 23, 2019	- -

Primary ciliary dyskinesia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 19, 2019

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in CCDC40 are known to be pathogenic (PMID: 21131974, 22693285, 23255504). This variant has been observed to segregate with primary ciliary dyskinesia in a family (PMID: 21131974) and has also been observed in individuals affected with primary ciliary diskinesia (PMID: 23255504, 22693285, 26228299). The variant is also known as c.1366C>T (p.R449X) in the literature. ClinVar contains an entry for this variant (Variation ID: 31072). This sequence change creates a premature translational stop signal (p.Arg449*) in the CCDC40 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	34
DANN	Benign	0.94
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.027	N
Vest4		0.27
GERP RS		-9.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs387907093; hg19: chr17-78032684;