17-80039965-GC-G

Variant names:

• chr17-80039965-GC-G
• rs397515393
• NM_017950.4:c.248delC

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_017950.4(CCDC40):​c.248delC​(p.Ala83ValfsTer84) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000563 in 1,600,206 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00059 (0 hom.)
• Consequence: CCDC40 NM_017950.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:21 O:1
• Conservation: PhyloP100: -4.80
• Publications: 18 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: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 17-80039965-GC-G is Pathogenic according to our data. Variant chr17-80039965-GC-G is described in ClinVar as Pathogenic. ClinVar VariationId is 31069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017950.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC40	NM_017950.4	MANE Select	c.248delC	p.Ala83ValfsTer84	frameshift	Exon 3 of 20	NP_060420.2
	CCDC40	NM_001243342.2		c.248delC	p.Ala83ValfsTer84	frameshift	Exon 3 of 18	NP_001230271.1
	CCDC40	NM_001330508.2		c.248delC	p.Ala83ValfsTer84	frameshift	Exon 3 of 11	NP_001317437.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC40	ENST00000397545.9	TSL:5 MANE Select	c.248delC	p.Ala83ValfsTer84	frameshift	Exon 3 of 20	ENSP00000380679.4
	CCDC40	ENST00000374876.4	TSL:1	c.248delC	p.Ala83ValfsTer84	frameshift	Exon 3 of 9	ENSP00000364010.4
	CCDC40	ENST00000897784.1		c.248delC	p.Ala83ValfsTer84	frameshift	Exon 3 of 21	ENSP00000567843.1

Frequencies

GnomAD3 genomes AF: 0.000270 AC: 41 AN: 152026 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000441 AC: 109 AN: 247240 AF XY: 0.000380

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000838

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.000594 AC: 860 AN: 1448062 Hom.: 0 Cov.: 32 AF XY: 0.000576 AC XY: 415 AN XY: 721066

African (AFR) AF: 0.000181 AC: 6 AN: 33186

American (AMR) AF: 0.000179 AC: 8 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85994

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.000752 AC: 827 AN: 1099350

Other (OTH) AF: 0.000234 AC: 14 AN: 59952

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.000256 AC XY: 19 AN XY: 74362

African (AFR) AF: 0.000169 AC: 7 AN: 41534

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10564

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000485 AC: 33 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000450 Hom.: 0

Bravo AF: 0.000321

Asia WGS AF: 0.000289 AC: 2 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.000711

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	Primary ciliary dyskinesia 15 (9)
6	-	-	not provided (6)
6	-	-	Primary ciliary dyskinesia (6)
1	-	-	CCDC40-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-4.8
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs397515393; hg19: chr17-78013764; COSMIC: COSV106091390; COSMIC: COSV106091390;