rs141343307

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_017950.4(CCDC40):c.2251C>A(p.Pro751Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00221 in 1,613,934 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0017 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0023 ( 17 hom. )

Consequence

CCDC40
NM_017950.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 5.60

Publications

4 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 -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07741755).

BP6

Variant 17-80086018-C-A is Benign according to our data. Variant chr17-80086018-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 260958.

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.00227 (3314/1461740) while in subpopulation SAS AF = 0.00471 (406/86250). AF 95% confidence interval is 0.00433. There are 17 homozygotes in GnomAdExome4. There are 1727 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017950.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC40	NM_017950.4	MANE Select	c.2251C>A	p.Pro751Thr	missense	Exon 14 of 20	NP_060420.2
	CCDC40	NM_001243342.2		c.2251C>A	p.Pro751Thr	missense	Exon 14 of 18	NP_001230271.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CCDC40	ENST00000397545.9	TSL:5 MANE Select	c.2251C>A	p.Pro751Thr	missense	Exon 14 of 20	ENSP00000380679.4
CCDC40	ENST00000574799.5	TSL:1	n.1788C>A		non_coding_transcript_exon	Exon 10 of 16
CCDC40	ENST00000374877.7	TSL:5	c.2251C>A	p.Pro751Thr	missense	Exon 14 of 18	ENSP00000364011.3

Frequencies

GnomAD3 genomes

AF:

0.00171

AC:

260

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00229

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00250

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00227

AC:

567

AN:

249470

AF XY:

0.00260

show subpopulations

Gnomad AFR exome

AF:

0.000452

Gnomad AMR exome

AF:

0.000782

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000974

Gnomad NFE exome

AF:

0.00304

Gnomad OTH exome

AF:

0.00264

GnomAD4 exome

AF:

0.00227

AC:

3314

AN:

1461740

Hom.:

Cov.:

AF XY:

0.00237

AC XY:

1727

AN XY:

727174

show subpopulations

African (AFR)

AF:

0.000358

AC:

AN:

33474

American (AMR)

AF:

0.000760

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00471

AC:

406

AN:

86250

European-Finnish (FIN)

AF:

0.00114

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00457

AC:

AN:

5690

European-Non Finnish (NFE)

AF:

0.00238

AC:

2651

AN:

1111974

Other (OTH)

AF:

0.00187

AC:

113

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

186

371

557

742

928

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

192

288

384

480

<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:

0.00170

AC:

259

AN:

152194

Hom.:

Cov.:

AF XY:

0.00172

AC XY:

128

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.000506

AC:

AN:

41538

American (AMR)

AF:

0.00229

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5144

South Asian (SAS)

AF:

0.00394

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00250

AC:

170

AN:

68004

Other (OTH)

AF:

0.00142

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00206

Hom.:

Bravo

AF:

0.00160

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000265

AC:

ESP6500EA

AF:

0.00219

AC:

ExAC

AF:

0.00231

AC:

279

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00267

EpiControl

AF:

0.00344

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Primary ciliary dyskinesia (2)

Primary ciliary dyskinesia 15 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Uncertain

0.027

BayesDel_noAF

Pathogenic

0.27

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.88

M_CAP

Pathogenic

0.40

MetaRNN

Benign

0.077

MetaSVM

Uncertain

0.086

MutationAssessor

Uncertain

2.5

PhyloP100

5.6

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-7.5

REVEL

Uncertain

0.53

Sift

Pathogenic

0.0

Sift4G

Benign

0.067

Polyphen

1.0

Vest4

0.93

MVP

0.79

MPC

0.74

ClinPred

0.045

GERP RS

4.7

Varity_R

0.59

gMVP

0.51

Mutation Taster

=82/18

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over