rs116795025

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_017950.4(CCDC40):c.1132G>A(p.Ala378Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000578 in 1,582,168 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0032 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00030 ( 0 hom. )

Consequence

CCDC40
NM_017950.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.178

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:

ENSG00000289689 (HGNC:):

ENSG00000289689 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0043277442).

BP6

Variant 17-80050256-G-A is Benign according to our data. Variant chr17-80050256-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00322 (490/152282) while in subpopulation AFR AF = 0.0114 (474/41562). AF 95% confidence interval is 0.0106. There are 1 homozygotes in GnomAd4. There are 232 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CCDC40	NM_017950.4 link	c.1132G>A	p.Ala378Thr	missense_variant	Exon 7 of 20	ENST00000397545.9	NP_060420.2
CCDC40	NM_001243342.2 link	c.1132G>A	p.Ala378Thr	missense_variant	Exon 7 of 18		NP_001230271.1
CCDC40	NM_001330508.2 link	c.1132G>A	p.Ala378Thr	missense_variant	Exon 7 of 11		NP_001317437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC40	ENST00000397545.9 link	c.1132G>A	p.Ala378Thr	missense_variant	Exon 7 of 20	5	NM_017950.4	ENSP00000380679.4

Frequencies

GnomAD3 genomes

AF:

0.00321

AC:

488

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0114

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000675

AC:

129

AN:

191060

AF XY:

0.000575

show subpopulations

Gnomad AFR exome

AF:

0.0113

Gnomad AMR exome

AF:

0.000321

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000399

GnomAD4 exome

AF:

0.000297

AC:

425

AN:

1429886

Hom.:

Cov.:

AF XY:

0.000241

AC XY:

171

AN XY:

709098

show subpopulations

African (AFR)

AF:

0.0115

AC:

374

AN:

32566

American (AMR)

AF:

0.000379

AC:

AN:

39602

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25592

East Asian (EAS)

AF:

0.00

AC:

AN:

37776

South Asian (SAS)

AF:

0.0000362

AC:

AN:

82828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50290

Middle Eastern (MID)

AF:

0.000242

AC:

AN:

4132

European-Non Finnish (NFE)

AF:

0.00000273

AC:

AN:

1097988

Other (OTH)

AF:

0.000491

AC:

AN:

59112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

106

132

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.00322

AC:

490

AN:

152282

Hom.:

Cov.:

AF XY:

0.00312

AC XY:

232

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.0114

AC:

474

AN:

41562

American (AMR)

AF:

0.000849

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68020

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

106

132

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:

0.00155

Hom.:

Bravo

AF:

0.00363

ESP6500AA

AF:

0.0124

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000776

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Benign:2

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 16, 2018

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 specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

May 06, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.72

CADD

Benign

3.6

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.062

.;T;.;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.091

LIST_S2

Benign

0.60

T;T;T;T

MetaRNN

Benign

0.0043

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

L;L;L;L

PhyloP100

0.18

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.70

N;N;N;N

REVEL

Benign

0.033

Sift

Benign

0.52

T;T;T;T

Sift4G

Benign

0.36

T;T;T;T

Polyphen

0.045, 0.79

.;B;.;P

Vest4

0.23

MVP

0.067

MPC

0.17

ClinPred

0.0026

GERP RS

-1.7

Varity_R

0.025

gMVP

0.031

Mutation Taster

=98/2

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over