17-80090346-A-ACACGGGACGCGCGCAGGCACGTGCACGAACAACAC

Variant names:

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

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_3041insCACGGGACGCGCGCAGGCACGTGCACGAACAACAC​(p.Arg1014ThrfsTer40) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. 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: 𝑓 0.000052 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000094 (9 hom.)
  • Failed GnomAD Quality Control
• Consequence: CCDC40 NM_001243342.2 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0180
• Publications: 7 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+463insCACGGGACGCGCGCAGGCACGTGCACGAACAACAC		intron	N/A	NP_060420.2
	CCDC40	NM_001243342.2		c.3040_3041insCACGGGACGCGCGCAGGCACGTGCACGAACAACAC	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+463insCACGGGACGCGCGCAGGCACGTGCACGAACAACAC		intron	N/A	ENSP00000380679.4	Q4G0X9-1
	CCDC40	ENST00000574799.5	TSL:1	n.2369+462_2369+463insCACGGGACGCGCGCAGGCACGTGCACGAACAACAC		intron	N/A
	CCDC40	ENST00000374877.7	TSL:5	c.3040_3041insCACGGGACGCGCGCAGGCACGTGCACGAACAACAC	p.Arg1014ThrfsTer40	frameshift	Exon 18 of 18	ENSP00000364011.3	Q4G0X9-2

Frequencies

GnomAD3 genomes AF: 0.0000517 AC: 1 AN: 19356 Hom.: 0 Cov.: 0

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: 0.000138

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000354 AC: 23 AN: 65002 AF XY: 0.000339

Gnomad AFR exome AF: 0.000843

Gnomad AMR exome AF: 0.000153

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00199

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000218

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000941 AC: 39 AN: 414252 Hom.: 9 Cov.: 43 AF XY: 0.000109 AC XY: 23 AN XY: 210730

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000315 AC: 4 AN: 12706

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

Ashkenazi Jewish (ASJ) AF: 0.000130 AC: 1 AN: 7698

East Asian (EAS) AF: 0.0000634 AC: 1 AN: 15784

South Asian (SAS) AF: 0.000172 AC: 5 AN: 29050

European-Finnish (FIN) AF: 0.000194 AC: 3 AN: 15482

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

European-Non Finnish (NFE) AF: 0.0000813 AC: 24 AN: 295310

Other (OTH) AF: 0.0000517 AC: 1 AN: 19340

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000376076), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000517 AC: 1 AN: 19356 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 9544

African (AFR) AF: 0.00 AC: 0 AN: 6254

American (AMR) AF: 0.00 AC: 0 AN: 3176

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 270

East Asian (EAS) AF: 0.00 AC: 0 AN: 870

South Asian (SAS) AF: 0.00 AC: 0 AN: 370

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 768

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 16

European-Non Finnish (NFE) AF: 0.000138 AC: 1 AN: 7226

Other (OTH) AF: 0.00 AC: 0 AN: 240

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.018
Mutation Taster		=191/9	polymorphism

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;