17-80081958-C-T

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.1889C>T(p.Ala630Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 1,613,548 control chromosomes in the GnomAD database, including 10,044 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. A630A) has been classified as Benign.

Frequency

Genomes: 𝑓 0.085 ( 641 hom., cov: 32)

Exomes 𝑓: 0.11 ( 9403 hom. )

Consequence

CCDC40
NM_017950.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.582

Publications

6 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018564463).

BP6

Variant 17-80081958-C-T is Benign according to our data. Variant chr17-80081958-C-T is described in ClinVar as Benign. ClinVar VariationId is 162849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.115 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC40	NM_017950.4 link	c.1889C>T	p.Ala630Val	missense_variant	Exon 12 of 20	ENST00000397545.9	NP_060420.2
CCDC40	NM_001243342.2 link	c.1889C>T	p.Ala630Val	missense_variant	Exon 12 of 18		NP_001230271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CCDC40	ENST00000397545.9 link	c.1889C>T	p.Ala630Val	missense_variant	Exon 12 of 20	5	NM_017950.4	ENSP00000380679.4
CCDC40	ENST00000574799.5 link	n.1426C>T		non_coding_transcript_exon_variant	Exon 8 of 16	1
CCDC40	ENST00000374877.7 link	c.1889C>T	p.Ala630Val	missense_variant	Exon 12 of 18	5		ENSP00000364011.3
CCDC40	ENST00000572253.5 link	n.516C>T		non_coding_transcript_exon_variant	Exon 1 of 6	2

Frequencies

GnomAD3 genomes

AF:

0.0854

AC:

12977

AN:

151938

Hom.:

642

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0448

Gnomad AMI

AF:

0.103

Gnomad AMR

AF:

0.0585

Gnomad ASJ

AF:

0.0974

Gnomad EAS

AF:

0.000588

Gnomad SAS

AF:

0.0553

Gnomad FIN

AF:

0.130

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.117

Gnomad OTH

AF:

0.0823

GnomAD2 exomes

AF:

0.0901

AC:

22430

AN:

248870

AF XY:

0.0934

show subpopulations

Gnomad AFR exome

AF:

0.0440

Gnomad AMR exome

AF:

0.0470

Gnomad ASJ exome

AF:

0.0973

Gnomad EAS exome

AF:

0.000167

Gnomad FIN exome

AF:

0.138

Gnomad NFE exome

AF:

0.121

Gnomad OTH exome

AF:

0.101

GnomAD4 exome

AF:

0.109

AC:

158777

AN:

1461492

Hom.:

9403

Cov.:

AF XY:

0.108

AC XY:

78411

AN XY:

727040

show subpopulations

African (AFR)

AF:

0.0430

AC:

1438

AN:

33474

American (AMR)

AF:

0.0487

AC:

2176

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.0977

AC:

2552

AN:

26130

East Asian (EAS)

AF:

0.000327

AC:

AN:

39696

South Asian (SAS)

AF:

0.0618

AC:

5332

AN:

86210

European-Finnish (FIN)

AF:

0.141

AC:

7550

AN:

53406

Middle Eastern (MID)

AF:

0.0865

AC:

499

AN:

5768

European-Non Finnish (NFE)

AF:

0.120

AC:

133332

AN:

1111726

Other (OTH)

AF:

0.0975

AC:

5885

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

8259

16519

24778

33038

41297

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4756

9512

14268

19024

23780

<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:

0.0853

AC:

12976

AN:

152056

Hom.:

641

Cov.:

AF XY:

0.0844

AC XY:

6270

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.0447

AC:

1858

AN:

41534

American (AMR)

AF:

0.0584

AC:

893

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0974

AC:

338

AN:

3470

East Asian (EAS)

AF:

0.000589

AC:

AN:

5090

South Asian (SAS)

AF:

0.0546

AC:

263

AN:

4820

European-Finnish (FIN)

AF:

0.130

AC:

1379

AN:

10594

Middle Eastern (MID)

AF:

0.0612

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.117

AC:

7957

AN:

67938

Other (OTH)

AF:

0.0819

AC:

173

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

595

1190

1786

2381

2976

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

148

296

444

592

740

<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:

0.107

Hom.:

1734

Bravo

AF:

0.0793

ExAC

AF:

0.0909

AC:

11014

Asia WGS

AF:

0.0270

AC:

AN:

3478

EpiCase

AF:

0.113

EpiControl

AF:

0.119

ClinVar

Significance: Benign

Submissions summary: Benign:6

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

Ala630Val in exon 12 of CCDC40: This variant is not expected to have clinical si gnificance because it has been identified in 11.3% (21/186) of Finnish chromosom es from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.nih. gov/projects/SNP; dbSNP rs61749058). -

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

Benign:1

Jul 07, 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. -

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

0.085

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.52

CADD

Benign

0.29

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.11

.;T

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.058

LIST_S2

Benign

0.62

T;T

MetaRNN

Benign

0.0019

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

M;M

PhyloP100

-0.58

PrimateAI

Benign

0.23

PROVEAN

Benign

-1.7

N;N

REVEL

Benign

0.028

Sift

Benign

0.22

T;T

Sift4G

Benign

0.44

T;T

Polyphen

0.75

.;P

Vest4

0.12

MPC

0.18

ClinPred

0.010

GERP RS

0.23

Varity_R

0.041

gMVP

0.10

Mutation Taster

=97/3

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