chr17-80090346-A-AC

Variant names:

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

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_3041insC​(p.Arg1014ThrfsTer80) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. 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 0.0013 (1 hom., cov: 0)
  • Exomes 𝑓: 0.00032 (15 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+463insC		intron	N/A	NP_060420.2
	CCDC40	NM_001243342.2		c.3040_3041insC	p.Arg1014ThrfsTer80	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+463insC		intron	N/A	ENSP00000380679.4	Q4G0X9-1
	CCDC40	ENST00000574799.5	TSL:1	n.2369+462_2369+463insC		intron	N/A
	CCDC40	ENST00000374877.7	TSL:5	c.3040_3041insC	p.Arg1014ThrfsTer80	frameshift	Exon 18 of 18	ENSP00000364011.3	Q4G0X9-2

Frequencies

GnomAD3 genomes AF: 0.00129 AC: 25 AN: 19358 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.00384

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000315

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000316 AC: 131 AN: 414012 Hom.: 15 Cov.: 43 AF XY: 0.000275 AC XY: 58 AN XY: 210622

African (AFR) AF: 0.00598 AC: 76 AN: 12704

American (AMR) AF: 0.000176 AC: 3 AN: 17050

Ashkenazi Jewish (ASJ) AF: 0.000260 AC: 2 AN: 7696

East Asian (EAS) AF: 0.00 AC: 0 AN: 15772

South Asian (SAS) AF: 0.000207 AC: 6 AN: 29040

European-Finnish (FIN) AF: 0.000129 AC: 2 AN: 15482

Middle Eastern (MID) AF: 0.000549 AC: 1 AN: 1822

European-Non Finnish (NFE) AF: 0.000115 AC: 34 AN: 295114

Other (OTH) AF: 0.000362 AC: 7 AN: 19332

GnomAD4 genome AF: 0.00129 AC: 25 AN: 19358 Hom.: 1 Cov.: 0 AF XY: 0.00157 AC XY: 15 AN XY: 9546

African (AFR) AF: 0.00384 AC: 24 AN: 6256

American (AMR) AF: 0.000315 AC: 1 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: 0.00 AC: 0 AN: 7226

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

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.018
Mutation Taster		=172/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs10693712; hg19: chr17-78064145;