chr17-80049923-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_017950.4(CCDC40):c.873C>T(p.Phe291Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0916 in 1,613,484 control chromosomes in the GnomAD database, including 7,538 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 835 hom., cov: 31)

Exomes 𝑓: 0.091 ( 6703 hom. )

Consequence

CCDC40
NM_017950.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.21

Publications

17 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:

ENSG00000289689 (HGNC:):

ENSG00000289689 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

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

BP6

Variant 17-80049923-C-T is Benign according to our data. Variant chr17-80049923-C-T is described in ClinVar as Benign. ClinVar VariationId is 178708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.21 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.153 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC40	NM_017950.4 link	c.873C>T	p.Phe291Phe	synonymous_variant	Exon 6 of 20	ENST00000397545.9	NP_060420.2	Q4G0X9-1
CCDC40	NM_001243342.2 link	c.873C>T	p.Phe291Phe	synonymous_variant	Exon 6 of 18		NP_001230271.1	Q4G0X9-2
CCDC40	NM_001330508.2 link	c.873C>T	p.Phe291Phe	synonymous_variant	Exon 6 of 11		NP_001317437.1	Q4G0X9-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC40	ENST00000397545.9 link	c.873C>T	p.Phe291Phe	synonymous_variant	Exon 6 of 20	5	NM_017950.4	ENSP00000380679.4		Q4G0X9-1

Frequencies

GnomAD3 genomes

AF:

0.100

AC:

15268

AN:

151974

Hom.:

837

Cov.:

show subpopulations

Gnomad AFR

AF:

0.114

Gnomad AMI

AF:

0.0176

Gnomad AMR

AF:

0.0651

Gnomad ASJ

AF:

0.133

Gnomad EAS

AF:

0.162

Gnomad SAS

AF:

0.112

Gnomad FIN

AF:

0.110

Gnomad MID

AF:

0.178

Gnomad NFE

AF:

0.0918

Gnomad OTH

AF:

0.114

GnomAD2 exomes

AF:

0.0991

AC:

24721

AN:

249498

AF XY:

0.102

show subpopulations

Gnomad AFR exome

AF:

0.114

Gnomad AMR exome

AF:

0.0525

Gnomad ASJ exome

AF:

0.132

Gnomad EAS exome

AF:

0.162

Gnomad FIN exome

AF:

0.110

Gnomad NFE exome

AF:

0.0883

Gnomad OTH exome

AF:

0.110

GnomAD4 exome

AF:

0.0907

AC:

132589

AN:

1461390

Hom.:

6703

Cov.:

AF XY:

0.0924

AC XY:

67204

AN XY:

727016

show subpopulations

African (AFR)

AF:

0.115

AC:

3859

AN:

33478

American (AMR)

AF:

0.0563

AC:

2519

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.130

AC:

3405

AN:

26134

East Asian (EAS)

AF:

0.182

AC:

7206

AN:

39690

South Asian (SAS)

AF:

0.123

AC:

10632

AN:

86242

European-Finnish (FIN)

AF:

0.110

AC:

5878

AN:

53416

Middle Eastern (MID)

AF:

0.144

AC:

829

AN:

5764

European-Non Finnish (NFE)

AF:

0.0830

AC:

92283

AN:

1111566

Other (OTH)

AF:

0.0990

AC:

5978

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

6894

13787

20681

27574

34468

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3418

6836

10254

13672

17090

<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:

0.100

AC:

15264

AN:

152094

Hom.:

835

Cov.:

AF XY:

0.102

AC XY:

7574

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.114

AC:

4727

AN:

41494

American (AMR)

AF:

0.0650

AC:

994

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.133

AC:

461

AN:

3464

East Asian (EAS)

AF:

0.162

AC:

834

AN:

5144

South Asian (SAS)

AF:

0.112

AC:

537

AN:

4812

European-Finnish (FIN)

AF:

0.110

AC:

1163

AN:

10580

Middle Eastern (MID)

AF:

0.163

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0918

AC:

6244

AN:

67998

Other (OTH)

AF:

0.114

AC:

240

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

670

1341

2011

2682

3352

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

186

372

558

744

930

<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:

0.0951

Hom.:

846

Bravo

AF:

0.0962

Asia WGS

AF:

0.118

AC:

410

AN:

3478

EpiCase

AF:

0.0938

EpiControl

AF:

0.0921

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Phe291Phe in exon 6 of CCDC40: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 10.5% (417/3954) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2289531). -

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 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

Jul 05, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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. -

Jul 14, 2021

Genome-Nilou Lab

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

-0.33

CADD

Benign

8.3

(source)

DANN

Benign

0.70

PhyloP100

1.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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