rs1982243

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_017950.4(CCDC40):c.2868G>A(p.Lys956=) variant causes a synonymous change. The variant allele was found at a frequency of 0.0305 in 1,614,018 control chromosomes in the GnomAD database, including 1,150 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.032 ( 114 hom., cov: 34)

Exomes 𝑓: 0.030 ( 1036 hom. )

Consequence

CCDC40
NM_017950.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.88

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.33).

BP6

Variant 17-80095298-G-A is Benign according to our data. Variant chr17-80095298-G-A is described in ClinVar as [Benign]. Clinvar id is 226492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80095298-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.122 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC40	NM_017950.4 linkuse as main transcript	c.2868G>A	p.Lys956=	synonymous_variant	18/20	ENST00000397545.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC40	ENST00000397545.9 linkuse as main transcript	c.2868G>A	p.Lys956=	synonymous_variant	18/20	5	NM_017950.4	P2	Q4G0X9-1
CCDC40	ENST00000574799.5 linkuse as main transcript	n.2405G>A		non_coding_transcript_exon_variant	14/16	1
CCDC40	ENST00000572253.5 linkuse as main transcript	n.3119G>A		non_coding_transcript_exon_variant	5/6	2
CCDC40	ENST00000575431.1 linkuse as main transcript	n.512G>A		non_coding_transcript_exon_variant	4/4	3

Frequencies

GnomAD3 genomes

AF:

0.0323

AC:

4911

AN:

152268

Hom.:

115

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0219

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0254

Gnomad ASJ

AF:

0.0291

Gnomad EAS

AF:

0.130

Gnomad SAS

AF:

0.0583

Gnomad FIN

AF:

0.0417

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0295

Gnomad OTH

AF:

0.0411

GnomAD3 exomes

AF:

0.0379

AC:

9432

AN:

249086

Hom.:

263

AF XY:

0.0391

AC XY:

5285

AN XY:

135308

show subpopulations

Gnomad AFR exome

AF:

0.0228

Gnomad AMR exome

AF:

0.0181

Gnomad ASJ exome

AF:

0.0313

Gnomad EAS exome

AF:

0.126

Gnomad SAS exome

AF:

0.0516

Gnomad FIN exome

AF:

0.0423

Gnomad NFE exome

AF:

0.0280

Gnomad OTH exome

AF:

0.0380

GnomAD4 exome

AF:

0.0304

AC:

44395

AN:

1461632

Hom.:

1036

Cov.:

AF XY:

0.0312

AC XY:

22699

AN XY:

727110

show subpopulations

Gnomad4 AFR exome

AF:

0.0208

Gnomad4 AMR exome

AF:

0.0194

Gnomad4 ASJ exome

AF:

0.0308

Gnomad4 EAS exome

AF:

0.139

Gnomad4 SAS exome

AF:

0.0500

Gnomad4 FIN exome

AF:

0.0414

Gnomad4 NFE exome

AF:

0.0248

Gnomad4 OTH exome

AF:

0.0375

GnomAD4 genome

AF:

0.0322

AC:

4908

AN:

152386

Hom.:

114

Cov.:

AF XY:

0.0339

AC XY:

2528

AN XY:

74524

show subpopulations

Gnomad4 AFR

AF:

0.0219

Gnomad4 AMR

AF:

0.0253

Gnomad4 ASJ

AF:

0.0291

Gnomad4 EAS

AF:

0.130

Gnomad4 SAS

AF:

0.0586

Gnomad4 FIN

AF:

0.0417

Gnomad4 NFE

AF:

0.0295

Gnomad4 OTH

AF:

0.0421

Alfa

AF:

0.0289

Hom.:

Bravo

AF:

0.0292

Asia WGS

AF:

0.0790

AC:

275

AN:

3478

EpiCase

AF:

0.0282

EpiControl

AF:

0.0290

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 02, 2015	p.Lys956Lys in exon 18 of CCDC40: This variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 3.7% (4610/11952 4) of all ethnicity chromosomes by the Exome Aggregation Consortium (ExAC, http: //exac.broadinstitute.org; dbSNP rs1982243). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Primary ciliary dyskinesia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 12, 2016	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:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

- -

Primary ciliary dyskinesia 15

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

BayesDel_noAF

Benign

-0.33

Cadd

Benign

9.1

Dann

Benign

0.61

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over