17-80048579-C-G

Position:

chr17-80048579-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_017950.4(CCDC40):c.677-4C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.237 in 1,611,000 control chromosomes in the GnomAD database, including 47,727 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.20 ( 3588 hom., cov: 31)

Exomes 𝑓: 0.24 ( 44139 hom. )

Consequence

CCDC40
NM_017950.4 splice_region, intron

Scores

Splicing: ADA: 0.00001481

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -1.87

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:

CCDC40 (HGNC:):

CCDC40 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.95).

BP6

Variant 17-80048579-C-G is Benign according to our data. Variant chr17-80048579-C-G is described in ClinVar as [Benign]. Clinvar id is 162846.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80048579-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.361 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
CCDC40	NM_017950.4 linkuse as main transcript	c.677-4C>G	splice_region_variant, intron_variant	ENST00000397545.9	NP_060420.2	Q4G0X9-1
CCDC40	NM_001243342.2 linkuse as main transcript	c.677-4C>G	splice_region_variant, intron_variant		NP_001230271.1	Q4G0X9-2
CCDC40	NM_001330508.2 linkuse as main transcript	c.677-4C>G	splice_region_variant, intron_variant		NP_001317437.1	Q4G0X9-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC40	ENST00000397545.9 linkuse as main transcript	c.677-4C>G		splice_region_variant, intron_variant		5	NM_017950.4	ENSP00000380679.4		Q4G0X9-1

Frequencies

GnomAD3 genomes

AF:

0.196

AC:

29788

AN:

152026

Hom.:

3583

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0545

Gnomad AMI

AF:

0.249

Gnomad AMR

AF:

0.292

Gnomad ASJ

AF:

0.188

Gnomad EAS

AF:

0.374

Gnomad SAS

AF:

0.209

Gnomad FIN

AF:

0.218

Gnomad MID

AF:

0.101

Gnomad NFE

AF:

0.242

Gnomad OTH

AF:

0.200

GnomAD3 exomes

AF:

0.238

AC:

58601

AN:

245724

Hom.:

7656

AF XY:

0.235

AC XY:

31392

AN XY:

133758

show subpopulations

Gnomad AFR exome

AF:

0.0466

Gnomad AMR exome

AF:

0.304

Gnomad ASJ exome

AF:

0.183

Gnomad EAS exome

AF:

0.396

Gnomad SAS exome

AF:

0.205

Gnomad FIN exome

AF:

0.218

Gnomad NFE exome

AF:

0.238

Gnomad OTH exome

AF:

0.217

GnomAD4 exome

AF:

0.242

AC:

352656

AN:

1458856

Hom.:

44139

Cov.:

AF XY:

0.241

AC XY:

174974

AN XY:

725898

show subpopulations

Gnomad4 AFR exome

AF:

0.0423

Gnomad4 AMR exome

AF:

0.303

Gnomad4 ASJ exome

AF:

0.184

Gnomad4 EAS exome

AF:

0.327

Gnomad4 SAS exome

AF:

0.208

Gnomad4 FIN exome

AF:

0.220

Gnomad4 NFE exome

AF:

0.248

Gnomad4 OTH exome

AF:

0.229

GnomAD4 genome

AF:

0.196

AC:

29808

AN:

152144

Hom.:

3588

Cov.:

AF XY:

0.199

AC XY:

14798

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.0544

Gnomad4 AMR

AF:

0.293

Gnomad4 ASJ

AF:

0.188

Gnomad4 EAS

AF:

0.375

Gnomad4 SAS

AF:

0.211

Gnomad4 FIN

AF:

0.218

Gnomad4 NFE

AF:

0.242

Gnomad4 OTH

AF:

0.203

Alfa

AF:

0.172

Hom.:

621

Bravo

AF:

0.194

EpiCase

AF:

0.238

EpiControl

AF:

0.234

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	677-4C>G in intron 4 of CCDC40: This variant is not expected to have clinical si gnificance because it is not located within the conserved splice consensus seque nce. It has been identified in 23.3% (1932/8296) of European American chromosome s from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.w ashington.edu/EVS; dbSNP rs2289530). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Primary ciliary dyskinesia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 08, 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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -

Primary ciliary dyskinesia 15

Benign:2

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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

0.041

DANN

Benign

0.35

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000015

dbscSNV1_RF

Benign

0.0

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