17-80090346-A-ACACGGGACGCGCGCAGGCAAGTGCACGAACAACAC

Variant names:

• chr17-80090346-A-ACACGGGACGCGCGCAGGCAAGTGCACGAACAACAC
• rs10693712
• NM_017950.4:c.2832+462_2832+463insCACGGGACGCGCGCAGGCAAGTGCACGAACAACAC

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_001243342.2(CCDC40):​c.3040_3041insCACGGGACGCGCGCAGGCAAGTGCACGAACAACAC​(p.Arg1014ThrfsTer40) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000241 in 414,270 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 INS_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. Synonymous variant affecting the same amino acid position (i.e. R1014R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: CCDC40 NM_001243342.2 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0180
• 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: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Ambry Genetics, 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: Uncertain_significance. The variant received 2 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0168 CDS is truncated, and there are 2 pathogenic variants in the truncated region.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001243342.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC40	NM_017950.4	MANE Select	c.2832+462_2832+463insCACGGGACGCGCGCAGGCAAGTGCACGAACAACAC		intron	N/A	NP_060420.2
	CCDC40	NM_001243342.2		c.3040_3041insCACGGGACGCGCGCAGGCAAGTGCACGAACAACAC	p.Arg1014ThrfsTer40	frameshift	Exon 18 of 18	NP_001230271.1	Q4G0X9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC40	ENST00000397545.9	TSL:5 MANE Select	c.2832+462_2832+463insCACGGGACGCGCGCAGGCAAGTGCACGAACAACAC		intron	N/A	ENSP00000380679.4	Q4G0X9-1
	CCDC40	ENST00000574799.5	TSL:1	n.2369+462_2369+463insCACGGGACGCGCGCAGGCAAGTGCACGAACAACAC		intron	N/A
	CCDC40	ENST00000374877.7	TSL:5	c.3040_3041insCACGGGACGCGCGCAGGCAAGTGCACGAACAACAC	p.Arg1014ThrfsTer40	frameshift	Exon 18 of 18	ENSP00000364011.3	Q4G0X9-2

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.00000241 AC: 1 AN: 414270 Hom.: 0 Cov.: 43 AF XY: 0.00000475 AC XY: 1 AN XY: 210742

African (AFR) AF: 0.00 AC: 0 AN: 12706

American (AMR) AF: 0.00 AC: 0 AN: 17058

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7698

East Asian (EAS) AF: 0.00 AC: 0 AN: 15784

South Asian (SAS) AF: 0.00 AC: 0 AN: 29056

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 15482

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1824

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 295318

Other (OTH) AF: 0.0000517 AC: 1 AN: 19344

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.018

Splicing

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

Other links and lift over

dbSNP: rs10693712; hg19: chr17-78064145;