17-80036664-T-G

Position:

• chr17-80036664-T-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_017950.4(CCDC40):​c.2T>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000153 in 1,308,422 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: CCDC40 NM_017950.4 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.13

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC40	NM_017950.4	c.2T>G	p.Met1?	start_lost	1/20	ENST00000397545.9	NP_060420.2
CCDC40	NM_001243342.2	c.2T>G	p.Met1?	start_lost	1/18		NP_001230271.1
CCDC40	NM_001330508.2	c.2T>G	p.Met1?	start_lost	1/11		NP_001317437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC40	ENST00000397545.9	c.2T>G	p.Met1?	start_lost	1/20	5	NM_017950.4	ENSP00000380679	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000153 AC: 2 AN: 1308422 Hom.: 0 Cov.: 31 AF XY: 0.00000155 AC XY: 1 AN XY: 643358

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: 0.00000192

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 20, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts a region of the CCDC40 protein in which other variant(s) (p.Pro13Leu) have been observed in individuals with CCDC40-related conditions (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Disruption of the initiator codon has been observed in individual(s) with clinical features of CCDC40-related conditions (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the CCDC40 mRNA. The next in-frame methionine is located at codon 31. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	25
DANN	Benign	0.96
DEOGEN2	Benign	0.039	.;T;.;.
Eigen	Benign	0.013
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.34	N
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Benign	-0.67	T
MutationTaster	Benign	1.0	D;D;D;D
PROVEAN	Benign	-0.96	N;N;N;N
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.97, 0.98	.;D;.;D
Vest4		0.85
MutPred		0.98		Loss of catalytic residue at M1 (P = 0.0026);Loss of catalytic residue at M1 (P = 0.0026);Loss of catalytic residue at M1 (P = 0.0026);Loss of catalytic residue at M1 (P = 0.0026);
MVP		0.67
ClinPred		0.70	D
GERP RS		1.8
Varity_R		0.96
gMVP		0.44

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-78010463;