rs1982243

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_017950.4(CCDC40):c.2868G>A(p.Lys956Lys) variant causes a synonymous change. The variant allele was found at a frequency of 0.0305 in 1,614,018 control chromosomes in the GnomAD database, including 1,150 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.032 ( 114 hom., cov: 34)

Exomes 𝑓: 0.030 ( 1036 hom. )

Consequence

CCDC40
NM_017950.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 3.88

Publications

10 publications found

Variant links:

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

CCDC40 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.33).

BP6

Variant 17-80095298-G-A is Benign according to our data. Variant chr17-80095298-G-A is described in ClinVar as Benign. ClinVar VariationId is 226492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.122 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC40	NM_017950.4 link	c.2868G>A	p.Lys956Lys	synonymous_variant	Exon 18 of 20	ENST00000397545.9	NP_060420.2	Q4G0X9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CCDC40	ENST00000397545.9 link	c.2868G>A	p.Lys956Lys	synonymous_variant	Exon 18 of 20	5	NM_017950.4	ENSP00000380679.4	Q4G0X9-1
CCDC40	ENST00000574799.5 link	n.2405G>A		non_coding_transcript_exon_variant	Exon 14 of 16	1
CCDC40	ENST00000572253.5 link	n.3119G>A		non_coding_transcript_exon_variant	Exon 5 of 6	2
CCDC40	ENST00000575431.1 link	n.512G>A		non_coding_transcript_exon_variant	Exon 4 of 4	3

Frequencies

GnomAD3 genomes

AF:

0.0323

AC:

4911

AN:

152268

Hom.:

115

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0219

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0254

Gnomad ASJ

AF:

0.0291

Gnomad EAS

AF:

0.130

Gnomad SAS

AF:

0.0583

Gnomad FIN

AF:

0.0417

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0295

Gnomad OTH

AF:

0.0411

GnomAD2 exomes

AF:

0.0379

AC:

9432

AN:

249086

AF XY:

0.0391

show subpopulations

Gnomad AFR exome

AF:

0.0228

Gnomad AMR exome

AF:

0.0181

Gnomad ASJ exome

AF:

0.0313

Gnomad EAS exome

AF:

0.126

Gnomad FIN exome

AF:

0.0423

Gnomad NFE exome

AF:

0.0280

Gnomad OTH exome

AF:

0.0380

GnomAD4 exome

AF:

0.0304

AC:

44395

AN:

1461632

Hom.:

1036

Cov.:

AF XY:

0.0312

AC XY:

22699

AN XY:

727110

show subpopulations

African (AFR)

AF:

0.0208

AC:

697

AN:

33478

American (AMR)

AF:

0.0194

AC:

866

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0308

AC:

805

AN:

26136

East Asian (EAS)

AF:

0.139

AC:

5520

AN:

39700

South Asian (SAS)

AF:

0.0500

AC:

4313

AN:

86256

European-Finnish (FIN)

AF:

0.0414

AC:

2202

AN:

53190

Middle Eastern (MID)

AF:

0.0324

AC:

187

AN:

5768

European-Non Finnish (NFE)

AF:

0.0248

AC:

27538

AN:

1111986

Other (OTH)

AF:

0.0375

AC:

2267

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

2556

5112

7667

10223

12779

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1080

2160

3240

4320

5400

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0322

AC:

4908

AN:

152386

Hom.:

114

Cov.:

AF XY:

0.0339

AC XY:

2528

AN XY:

74524

show subpopulations

African (AFR)

AF:

0.0219

AC:

910

AN:

41594

American (AMR)

AF:

0.0253

AC:

388

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0291

AC:

101

AN:

3472

East Asian (EAS)

AF:

0.130

AC:

673

AN:

5192

South Asian (SAS)

AF:

0.0586

AC:

283

AN:

4832

European-Finnish (FIN)

AF:

0.0417

AC:

443

AN:

10628

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0295

AC:

2007

AN:

68040

Other (OTH)

AF:

0.0421

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

261

522

784

1045

1306

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

186

248

310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0287

Hom.:

Bravo

AF:

0.0292

Asia WGS

AF:

0.0790

AC:

275

AN:

3478

EpiCase

AF:

0.0282

EpiControl

AF:

0.0290

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Sep 02, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Lys956Lys in exon 18 of CCDC40: This variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 3.7% (4610/11952 4) of all ethnicity chromosomes by the Exome Aggregation Consortium (ExAC, http: //exac.broadinstitute.org; dbSNP rs1982243). -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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 12, 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 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary ciliary dyskinesia 15

Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.33

CADD

Benign

9.1

(source)

DANN

Benign

0.61

PhyloP100

3.9

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over