17-80048579-C-G

Variant names:

• chr17-80048579-C-G
• rs2289530
• ENST00000574799.5:n.210C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000574799.5(CCDC40):​n.210C>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.237 in 1,611,000 control chromosomes in the GnomAD database, including 47,727 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3588 hom., cov: 31)
  • Exomes 𝑓: 0.24 (44139 hom.)
• Consequence: CCDC40 ENST00000574799.5 non_coding_transcript_exon
• Scores: Splicing: ADA: 0.00001481
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.87
• Publications: 13 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

ENSG00000289689 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 17-80048579-C-G is Benign according to our data. Variant chr17-80048579-C-G is described in ClinVar as Benign. ClinVar VariationId is 162846.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.361 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC40	NM_017950.4	c.677-4C>G		splice_region_variant, intron_variant	Intron 4 of 19	ENST00000397545.9	NP_060420.2
CCDC40	NM_001243342.2	c.677-4C>G		splice_region_variant, intron_variant	Intron 4 of 17		NP_001230271.1
CCDC40	NM_001330508.2	c.677-4C>G		splice_region_variant, intron_variant	Intron 4 of 10		NP_001317437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC40	ENST00000397545.9	c.677-4C>G		splice_region_variant, intron_variant	Intron 4 of 19	5	NM_017950.4	ENSP00000380679.4

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29788 AN: 152026 Hom.: 3583 Cov.: 31

Gnomad AFR AF: 0.0545

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.292

Gnomad ASJ AF: 0.188

Gnomad EAS AF: 0.374

Gnomad SAS AF: 0.209

Gnomad FIN AF: 0.218

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.200

GnomAD2 exomes AF: 0.238 AC: 58601 AN: 245724 AF XY: 0.235

Gnomad AFR exome AF: 0.0466

Gnomad AMR exome AF: 0.304

Gnomad ASJ exome AF: 0.183

Gnomad EAS exome AF: 0.396

Gnomad FIN exome AF: 0.218

Gnomad NFE exome AF: 0.238

Gnomad OTH exome AF: 0.217

GnomAD4 exome AF: 0.242 AC: 352656 AN: 1458856 Hom.: 44139 Cov.: 32 AF XY: 0.241 AC XY: 174974 AN XY: 725898

African (AFR) AF: 0.0423 AC: 1416 AN: 33444

American (AMR) AF: 0.303 AC: 13550 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 4807 AN: 26120

East Asian (EAS) AF: 0.327 AC: 12958 AN: 39650

South Asian (SAS) AF: 0.208 AC: 17901 AN: 86162

European-Finnish (FIN) AF: 0.220 AC: 11697 AN: 53092

Middle Eastern (MID) AF: 0.169 AC: 933 AN: 5512

European-Non Finnish (NFE) AF: 0.248 AC: 275592 AN: 1109988

Other (OTH) AF: 0.229 AC: 13802 AN: 60236

GnomAD4 genome AF: 0.196 AC: 29808 AN: 152144 Hom.: 3588 Cov.: 31 AF XY: 0.199 AC XY: 14798 AN XY: 74374

African (AFR) AF: 0.0544 AC: 2260 AN: 41536

American (AMR) AF: 0.293 AC: 4476 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 653 AN: 3470

East Asian (EAS) AF: 0.375 AC: 1933 AN: 5158

South Asian (SAS) AF: 0.211 AC: 1016 AN: 4818

European-Finnish (FIN) AF: 0.218 AC: 2313 AN: 10602

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.242 AC: 16473 AN: 67962

Other (OTH) AF: 0.203 AC: 427 AN: 2108

Alfa AF: 0.172 Hom.: 621

Bravo AF: 0.194

EpiCase AF: 0.238

EpiControl AF: 0.234

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

677-4C>G in intron 4 of CCDC40: This variant is not expected to have clinical si gnificance because it is not located within the conserved splice consensus seque nce. It has been identified in 23.3% (1932/8296) of European American chromosome s from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.w ashington.edu/EVS; dbSNP rs2289530). -

Primary ciliary dyskinesia Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 08, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary ciliary dyskinesia 15 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.041
DANN	Benign	0.35
PhyloP100		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000015
dbscSNV1_RF	Benign	0.0
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: rs2289530; hg19: chr17-78022378; COSMIC: COSV53896456; COSMIC: COSV53896456;