chr17-80088073-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_017950.4(CCDC40):c.2682G>A(p.Ala894Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 1,613,594 control chromosomes in the GnomAD database, including 198 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 15 hom., cov: 32)

Exomes 𝑓: 0.011 ( 183 hom. )

Consequence

CCDC40
NM_017950.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.923

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 17-80088073-G-A is Benign according to our data. Variant chr17-80088073-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 260962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.923 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.01 (1521/151990) while in subpopulation EAS AF = 0.0364 (188/5170). AF 95% confidence interval is 0.0321. There are 15 homozygotes in GnomAd4. There are 786 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 15 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC40	NM_017950.4 link	c.2682G>A	p.Ala894Ala	synonymous_variant	Exon 16 of 20	ENST00000397545.9	NP_060420.2	Q4G0X9-1
CCDC40	NM_001243342.2 link	c.2682G>A	p.Ala894Ala	synonymous_variant	Exon 16 of 18		NP_001230271.1	Q4G0X9-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC40	ENST00000397545.9 link	c.2682G>A	p.Ala894Ala	synonymous_variant	Exon 16 of 20	5	NM_017950.4	ENSP00000380679.4		Q4G0X9-1

Frequencies

GnomAD3 genomes

AF:

0.0100

AC:

1522

AN:

151872

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00610

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0115

Gnomad ASJ

AF:

0.00548

Gnomad EAS

AF:

0.0371

Gnomad SAS

AF:

0.00915

Gnomad FIN

AF:

0.0216

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00883

Gnomad OTH

AF:

0.00575

GnomAD2 exomes

AF:

0.0146

AC:

3643

AN:

249398

AF XY:

0.0132

show subpopulations

Gnomad AFR exome

AF:

0.00569

Gnomad AMR exome

AF:

0.0311

Gnomad ASJ exome

AF:

0.00477

Gnomad EAS exome

AF:

0.0352

Gnomad FIN exome

AF:

0.0217

Gnomad NFE exome

AF:

0.00997

Gnomad OTH exome

AF:

0.0127

GnomAD4 exome

AF:

0.0112

AC:

16403

AN:

1461604

Hom.:

183

Cov.:

AF XY:

0.0109

AC XY:

7890

AN XY:

727124

show subpopulations

African (AFR)

AF:

0.00436

AC:

146

AN:

33478

American (AMR)

AF:

0.0275

AC:

1229

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00524

AC:

137

AN:

26136

East Asian (EAS)

AF:

0.0510

AC:

2024

AN:

39696

South Asian (SAS)

AF:

0.00444

AC:

383

AN:

86250

European-Finnish (FIN)

AF:

0.0207

AC:

1103

AN:

53408

Middle Eastern (MID)

AF:

0.00208

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00964

AC:

10720

AN:

1111762

Other (OTH)

AF:

0.0107

AC:

649

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

861

1723

2584

3446

4307

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0100

AC:

1521

AN:

151990

Hom.:

Cov.:

AF XY:

0.0106

AC XY:

786

AN XY:

74278

show subpopulations

African (AFR)

AF:

0.00611

AC:

253

AN:

41428

American (AMR)

AF:

0.0116

AC:

177

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00548

AC:

AN:

3470

East Asian (EAS)

AF:

0.0364

AC:

188

AN:

5170

South Asian (SAS)

AF:

0.00916

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.0216

AC:

228

AN:

10552

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00883

AC:

600

AN:

67968

Other (OTH)

AF:

0.00569

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

152

229

305

381

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00896

Hom.:

Bravo

AF:

0.00991

Asia WGS

AF:

0.0360

AC:

124

AN:

3478

EpiCase

AF:

0.00643

EpiControl

AF:

0.00771

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

- -

Aug 05, 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

Apr 07, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Primary ciliary dyskinesia 15

Benign:2

Nov 01, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

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

-0.72

CADD

Benign

5.8

(source)

DANN

Benign

0.42

PhyloP100

0.92

Mutation Taster

=100/0

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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chr17-80088073-G-A

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