chr17-80086090-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_017950.4(CCDC40):c.2323G>A(p.Val775Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0862 in 1,614,060 control chromosomes in the GnomAD database, including 7,071 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V775V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.11 ( 1255 hom., cov: 32)

Exomes 𝑓: 0.083 ( 5816 hom. )

Consequence

CCDC40
NM_017950.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.64

Publications

13 publications found

Variant links:

COSMIC-nc: COSV107494471

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017687082).

BP6

Variant 17-80086090-G-A is Benign according to our data. Variant chr17-80086090-G-A is described in ClinVar as Benign. ClinVar VariationId is 162851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.203 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC40	NM_017950.4 link	c.2323G>A	p.Val775Met	missense_variant	Exon 14 of 20	ENST00000397545.9	NP_060420.2	Q4G0X9-1
CCDC40	NM_001243342.2 link	c.2323G>A	p.Val775Met	missense_variant	Exon 14 of 18		NP_001230271.1	Q4G0X9-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CCDC40	ENST00000397545.9 link	c.2323G>A	p.Val775Met	missense_variant	Exon 14 of 20	5	NM_017950.4	ENSP00000380679.4	Q4G0X9-1
CCDC40	ENST00000574799.5 link	n.1860G>A		non_coding_transcript_exon_variant	Exon 10 of 16	1
CCDC40	ENST00000374877.7 link	c.2323G>A	p.Val775Met	missense_variant	Exon 14 of 18	5		ENSP00000364011.3	Q4G0X9-2
CCDC40	ENST00000572253.5 link	n.950G>A		non_coding_transcript_exon_variant	Exon 3 of 6	2

Frequencies

GnomAD3 genomes

AF:

0.115

AC:

17475

AN:

152128

Hom.:

1251

Cov.:

show subpopulations

Gnomad AFR

AF:

0.207

Gnomad AMI

AF:

0.0713

Gnomad AMR

AF:

0.0645

Gnomad ASJ

AF:

0.104

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.0824

Gnomad FIN

AF:

0.115

Gnomad MID

AF:

0.166

Gnomad NFE

AF:

0.0819

Gnomad OTH

AF:

0.112

GnomAD2 exomes

AF:

0.0880

AC:

21937

AN:

249388

AF XY:

0.0886

show subpopulations

Gnomad AFR exome

AF:

0.211

Gnomad AMR exome

AF:

0.0525

Gnomad ASJ exome

AF:

0.106

Gnomad EAS exome

AF:

0.000612

Gnomad FIN exome

AF:

0.111

Gnomad NFE exome

AF:

0.0855

Gnomad OTH exome

AF:

0.0949

GnomAD4 exome

AF:

0.0832

AC:

121580

AN:

1461812

Hom.:

5816

Cov.:

AF XY:

0.0839

AC XY:

61034

AN XY:

727208

show subpopulations

African (AFR)

AF:

0.217

AC:

7252

AN:

33476

American (AMR)

AF:

0.0559

AC:

2498

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.105

AC:

2748

AN:

26136

East Asian (EAS)

AF:

0.000378

AC:

AN:

39700

South Asian (SAS)

AF:

0.0990

AC:

8543

AN:

86252

European-Finnish (FIN)

AF:

0.114

AC:

6062

AN:

53406

Middle Eastern (MID)

AF:

0.128

AC:

736

AN:

5744

European-Non Finnish (NFE)

AF:

0.0795

AC:

88388

AN:

1111986

Other (OTH)

AF:

0.0884

AC:

5338

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

6928

13856

20783

27711

34639

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3252

6504

9756

13008

16260

<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:

0.115

AC:

17488

AN:

152248

Hom.:

1255

Cov.:

AF XY:

0.114

AC XY:

8523

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.207

AC:

8603

AN:

41540

American (AMR)

AF:

0.0643

AC:

985

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.104

AC:

361

AN:

3472

East Asian (EAS)

AF:

0.000580

AC:

AN:

5170

South Asian (SAS)

AF:

0.0825

AC:

398

AN:

4824

European-Finnish (FIN)

AF:

0.115

AC:

1215

AN:

10600

Middle Eastern (MID)

AF:

0.173

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0819

AC:

5573

AN:

68014

Other (OTH)

AF:

0.111

AC:

234

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

791

1582

2373

3164

3955

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

204

408

612

816

1020

<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:

0.0909

Hom.:

1679

Bravo

AF:

0.115

TwinsUK

AF:

0.0771

AC:

286

ALSPAC

AF:

0.0815

AC:

314

ESP6500AA

AF:

0.185

AC:

775

ESP6500EA

AF:

0.0846

AC:

711

ExAC

AF:

0.0915

AC:

11069

Asia WGS

AF:

0.0530

AC:

186

AN:

3478

EpiCase

AF:

0.0858

EpiControl

AF:

0.0860

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

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

Val775Met in exon 14 of CCDC40: This variant is not expected to have clinical si gnificance because it has been identified in 18.5% (775/4194) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs60684213). -

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 27, 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:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.69

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.049

.;T

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.69

T;T

MetaRNN

Benign

0.0018

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

L;L

PhyloP100

1.6

PrimateAI

Benign

0.37

PROVEAN

Benign

0.74

N;N

REVEL

Benign

0.035

Sift

Benign

0.15

T;T

Sift4G

Benign

0.12

T;T

Polyphen

0.19

.;B

Vest4

0.080

MPC

0.21

ClinPred

0.0066

GERP RS

2.7

Varity_R

0.027

gMVP

0.11

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