17-80036684-GCGGGCCGGTAAGC-G

Variant names:

• chr17-80036684-GCGGGCCGGTAAGC-G
• rs771732758
• NM_017950.4:c.29+1_29+13delGTAAGCCGGGCCG

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_017950.4(CCDC40):​c.29+1_29+13delGTAAGCCGGGCCG variant causes a splice donor, splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000763 in 1,310,102 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: CCDC40 NM_017950.4 splice_donor, splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.31
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 15

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, Laboratory for Molecular Medicine
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autoimmune disease

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC40	NM_017950.4	c.29+1_29+13delGTAAGCCGGGCCG		splice_donor_variant, splice_region_variant, intron_variant	Intron 1 of 19	ENST00000397545.9	NP_060420.2
CCDC40	NM_001243342.2	c.29+1_29+13delGTAAGCCGGGCCG		splice_donor_variant, splice_region_variant, intron_variant	Intron 1 of 17		NP_001230271.1
CCDC40	NM_001330508.2	c.29+1_29+13delGTAAGCCGGGCCG		splice_donor_variant, splice_region_variant, intron_variant	Intron 1 of 10		NP_001317437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC40	ENST00000397545.9	c.29+1_29+13delGTAAGCCGGGCCG		splice_donor_variant, splice_region_variant, intron_variant	Intron 1 of 19	5	NM_017950.4	ENSP00000380679.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.63e-7 AC: 1 AN: 1310102 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 644020

African (AFR) AF: 0.00 AC: 0 AN: 27612

American (AMR) AF: 0.00 AC: 0 AN: 26818

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22812

East Asian (EAS) AF: 0.0000333 AC: 1 AN: 30070

South Asian (SAS) AF: 0.00 AC: 0 AN: 70400

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31796

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5172

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1041274

Other (OTH) AF: 0.00 AC: 0 AN: 54148

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs771732758; hg19: chr17-78010483;