rs139301500

Variant names:

• chr17-80095474-CAG-C
• rs139301500
• NM_017950.4:c.3021+24_3021+25delAG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_017950.4(CCDC40):​c.3021+24_3021+25delAG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0278 in 1,610,074 control chromosomes in the GnomAD database, including 679 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (38 hom., cov: 33)
  • Exomes 𝑓: 0.028 (641 hom.)
• Consequence: CCDC40 NM_017950.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.641
• 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 17-80095474-CAG-C is Benign according to our data. Variant chr17-80095474-CAG-C is described in ClinVar as [Likely_benign]. Clinvar id is 260966.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0209 (3187/152372) while in subpopulation NFE AF = 0.03 (2041/68036). AF 95% confidence interval is 0.0289. There are 38 homozygotes in GnomAd4. There are 1525 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 38 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC40	NM_017950.4	c.3021+24_3021+25delAG		intron_variant	Intron 18 of 19	ENST00000397545.9	NP_060420.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC40	ENST00000397545.9	c.3021+24_3021+25delAG		intron_variant	Intron 18 of 19	5	NM_017950.4	ENSP00000380679.4
CCDC40	ENST00000574799.5	n.2558+24_2558+25delAG		intron_variant	Intron 14 of 15	1
CCDC40	ENST00000572253.5	n.3272+24_3272+25delAG		intron_variant	Intron 5 of 5	2
CCDC40	ENST00000575431.1	n.*138_*139delAG		downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.0209 AC: 3187 AN: 152254 Hom.: 38 Cov.: 33

Gnomad AFR AF: 0.00603

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0215

Gnomad ASJ AF: 0.0357

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00889

Gnomad FIN AF: 0.0318

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0300

Gnomad OTH AF: 0.0258

GnomAD2 exomes AF: 0.0225 AC: 5480 AN: 243968 AF XY: 0.0229

Gnomad AFR exome AF: 0.00448

Gnomad AMR exome AF: 0.0140

Gnomad ASJ exome AF: 0.0343

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0369

Gnomad NFE exome AF: 0.0301

Gnomad OTH exome AF: 0.0268

GnomAD4 exome AF: 0.0285 AC: 41536 AN: 1457702 Hom.: 641 AF XY: 0.0280 AC XY: 20307 AN XY: 725368

African (AFR) AF: 0.00482 AC: 161 AN: 33380

American (AMR) AF: 0.0138 AC: 616 AN: 44548

Ashkenazi Jewish (ASJ) AF: 0.0356 AC: 930 AN: 26104

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39660

South Asian (SAS) AF: 0.0119 AC: 1024 AN: 86128

European-Finnish (FIN) AF: 0.0355 AC: 1890 AN: 53196

Middle Eastern (MID) AF: 0.0123 AC: 71 AN: 5766

European-Non Finnish (NFE) AF: 0.0318 AC: 35260 AN: 1108672

Other (OTH) AF: 0.0262 AC: 1581 AN: 60248

GnomAD4 genome AF: 0.0209 AC: 3187 AN: 152372 Hom.: 38 Cov.: 33 AF XY: 0.0205 AC XY: 1525 AN XY: 74512

African (AFR) AF: 0.00601 AC: 250 AN: 41594

American (AMR) AF: 0.0215 AC: 329 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.0357 AC: 124 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00890 AC: 43 AN: 4832

European-Finnish (FIN) AF: 0.0318 AC: 338 AN: 10620

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0300 AC: 2041 AN: 68036

Other (OTH) AF: 0.0256 AC: 54 AN: 2112

Alfa AF: 0.0276 Hom.: 7

Bravo AF: 0.0195

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jul 05, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.64
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs139301500; hg19: chr17-78069273;