rs2289533

Variant names:

• chr17-80050295-C-T
• rs2289533
• NM_017950.4:c.1159+12C>T

Variant summary

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

The NM_017950.4(CCDC40):​c.1159+12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.237 in 1,548,256 control chromosomes in the GnomAD database, including 45,677 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3592 hom., cov: 32)
  • Exomes 𝑓: 0.24 (42085 hom.)
• Consequence: CCDC40 NM_017950.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.684
• Publications: 12 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=-0.8).
• BP6: Variant 17-80050295-C-T is Benign according to our data. Variant chr17-80050295-C-T is described in ClinVar as Benign. ClinVar VariationId is 162847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.36 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC40	NM_017950.4	c.1159+12C>T		intron_variant	Intron 7 of 19	ENST00000397545.9	NP_060420.2
CCDC40	NM_001243342.2	c.1159+12C>T		intron_variant	Intron 7 of 17		NP_001230271.1
CCDC40	NM_001330508.2	c.1159+12C>T		intron_variant	Intron 7 of 10		NP_001317437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC40	ENST00000397545.9	c.1159+12C>T		intron_variant	Intron 7 of 19	5	NM_017950.4	ENSP00000380679.4

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29749 AN: 152010 Hom.: 3587 Cov.: 32

Gnomad AFR AF: 0.0540

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.292

Gnomad ASJ AF: 0.188

Gnomad EAS AF: 0.373

Gnomad SAS AF: 0.210

Gnomad FIN AF: 0.218

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.201

GnomAD2 exomes AF: 0.242 AC: 37159 AN: 153680 AF XY: 0.238

Gnomad AFR exome AF: 0.0427

Gnomad AMR exome AF: 0.303

Gnomad ASJ exome AF: 0.183

Gnomad EAS exome AF: 0.402

Gnomad FIN exome AF: 0.216

Gnomad NFE exome AF: 0.245

Gnomad OTH exome AF: 0.214

GnomAD4 exome AF: 0.241 AC: 337160 AN: 1396128 Hom.: 42085 Cov.: 33 AF XY: 0.241 AC XY: 166177 AN XY: 689096

African (AFR) AF: 0.0415 AC: 1311 AN: 31572

American (AMR) AF: 0.301 AC: 10778 AN: 35860

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 4641 AN: 25188

East Asian (EAS) AF: 0.318 AC: 11382 AN: 35820

South Asian (SAS) AF: 0.207 AC: 16459 AN: 79458

European-Finnish (FIN) AF: 0.221 AC: 10727 AN: 48604

Middle Eastern (MID) AF: 0.171 AC: 694 AN: 4066

European-Non Finnish (NFE) AF: 0.249 AC: 267915 AN: 1077734

Other (OTH) AF: 0.229 AC: 13253 AN: 57826

GnomAD4 genome AF: 0.196 AC: 29769 AN: 152128 Hom.: 3592 Cov.: 32 AF XY: 0.199 AC XY: 14781 AN XY: 74352

African (AFR) AF: 0.0539 AC: 2238 AN: 41534

American (AMR) AF: 0.293 AC: 4475 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 651 AN: 3466

East Asian (EAS) AF: 0.373 AC: 1925 AN: 5154

South Asian (SAS) AF: 0.212 AC: 1019 AN: 4814

European-Finnish (FIN) AF: 0.218 AC: 2309 AN: 10588

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

European-Non Finnish (NFE) AF: 0.242 AC: 16466 AN: 67962

Other (OTH) AF: 0.203 AC: 429 AN: 2114

Alfa AF: 0.223 Hom.: 11451

Bravo AF: 0.194

Asia WGS AF: 0.290 AC: 1007 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

1159+12C>T in intron 7 of CCDC40: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus seq uence. It has been identified in 21.4% (1740/8114) of European American chromoso mes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs .washington.edu/EVS; dbSNP rs2289533). -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary ciliary dyskinesia 15 Benign:2

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 12, 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. -

Primary ciliary dyskinesia Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.0
DANN	Benign	0.67
PhyloP100		0.68
Mutation Taster		=100/0	polymorphism (auto)

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: rs2289533; hg19: chr17-78024094;