17-80086207-C-T

Position:

chr17-80086207-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_017950.4(CCDC40):c.2440C>T(p.Arg814*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000871 in 1,606,720 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: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

CCDC40
NM_017950.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 2.27

Variant links:

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 links:

CCDC40 (HGNC:):

CCDC40 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 17-80086207-C-T is Pathogenic according to our data. Variant chr17-80086207-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 569156.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 linkuse as main transcript	c.2440C>T	p.Arg814*	stop_gained	14/20	ENST00000397545.9	NP_060420.2	Q4G0X9-1
CCDC40	NM_001243342.2 linkuse as main transcript	c.2440C>T	p.Arg814*	stop_gained	14/18		NP_001230271.1	Q4G0X9-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CCDC40	ENST00000397545.9 linkuse as main transcript	c.2440C>T	p.Arg814*	stop_gained	14/20	5	NM_017950.4	ENSP00000380679.4	Q4G0X9-1
CCDC40	ENST00000574799.5 linkuse as main transcript	n.1977C>T		non_coding_transcript_exon_variant	10/16	1
CCDC40	ENST00000374877.7 linkuse as main transcript	c.2440C>T	p.Arg814*	stop_gained	14/18	5		ENSP00000364011.3	Q4G0X9-2
CCDC40	ENST00000572253.5 linkuse as main transcript	n.1067C>T		non_coding_transcript_exon_variant	3/6	2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000877

AC:

AN:

228180

Hom.:

AF XY:

0.00000802

AC XY:

AN XY:

124708

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000307

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000598

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000825

AC:

AN:

1454562

Hom.:

Cov.:

AF XY:

0.00000830

AC XY:

AN XY:

723094

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000230

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000254

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000902

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.00000830

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 09, 2023	This premature translational stop signal has been observed in individual(s) with primary ciliary dyskinesia (PMID: 21131974, 23255504). This sequence change creates a premature translational stop signal (p.Arg814*) in the CCDC40 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CCDC40 are known to be pathogenic (PMID: 21131974, 22693285, 23255504). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. ClinVar contains an entry for this variant (Variation ID: 569156). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 28, 2021	The p.R814* pathogenic mutation (also known as c.2440C>T), located in coding exon 14 of the CCDC40 gene, results from a C to T substitution at nucleotide position 2440. This changes the amino acid from an arginine to a stop codon within coding exon 14. This variant has been detected in multiple individuals with primary ciliary dyskinesia, in the homozygous state and in the compound heterozygous state with another pathogenic CCDC40 variant (Antony D et al. Hum Mutat, 2013 Mar;34:462-72; Becker-Heck A et al. Nat Genet, 2011 Jan;43:79-84; Zariwala MA et al. Am J Hum Genet, 2013 Aug;93:336-45). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Combined immunodeficiency due to DOCK8 deficiency

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

Mar 01, 2023

The stop gained c.2440C>T (p.Arg814Ter) variant in CCDC40 gene has been reported in homozygous state in multiple individuals affected with Ciliary dyskinesia (Liu L et al. 2021; Antony D et al. 2013; Becker-Heck A et al. 2011). The p.Arg814Ter variant has allele frequency 0.0009% in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submitters). The nucleotide change c.2440C>T in CCDC40 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss-of-function variants in CCDC40 are known to be pathogenic (Antony D et al. 2013). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Benign

-0.0061

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.69

Vest4

0.33

GERP RS

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over