Genetic Variant CCDC40:c.*15T>C (chr17-80099790-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

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

The NM_017950.4(CCDC40):c.*15T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.294 in 1,610,396 control chromosomes in the GnomAD database, including 73,542 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.35 ( 10337 hom., cov: 32)

Exomes 𝑓: 0.29 ( 63205 hom. )

Consequence

CCDC40
NM_017950.4 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.649

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 17-80099790-T-C is Benign according to our data. Variant chr17-80099790-T-C is described in ClinVar as [Benign]. Clinvar id is 162853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80099790-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.511 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC40	NM_017950.4 link	c.*15T>C		3_prime_UTR_variant	Exon 20 of 20	ENST00000397545.9	NP_060420.2	Q4G0X9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC40	ENST00000397545.9 link	c.*15T>C		3_prime_UTR_variant	Exon 20 of 20	5	NM_017950.4	ENSP00000380679.4		Q4G0X9-1
CCDC40	ENST00000574799.5 link	n.2981T>C		non_coding_transcript_exon_variant	Exon 16 of 16	1

Frequencies

GnomAD3 genomes

AF:

0.352

AC:

53366

AN:

151808

Hom.:

10320

Cov.:

show subpopulations

Gnomad AFR

AF:

0.517

Gnomad AMI

AF:

0.337

Gnomad AMR

AF:

0.216

Gnomad ASJ

AF:

0.257

Gnomad EAS

AF:

0.424

Gnomad SAS

AF:

0.326

Gnomad FIN

AF:

0.333

Gnomad MID

AF:

0.354

Gnomad NFE

AF:

0.287

Gnomad OTH

AF:

0.328

GnomAD3 exomes

AF:

0.302

AC:

73977

AN:

245030

Hom.:

11950

AF XY:

0.305

AC XY:

40779

AN XY:

133664

show subpopulations

Gnomad AFR exome

AF:

0.521

Gnomad AMR exome

AF:

0.159

Gnomad ASJ exome

AF:

0.266

Gnomad EAS exome

AF:

0.409

Gnomad SAS exome

AF:

0.333

Gnomad FIN exome

AF:

0.329

Gnomad NFE exome

AF:

0.289

Gnomad OTH exome

AF:

0.309

GnomAD4 exome

AF:

0.288

AC:

420697

AN:

1458470

Hom.:

63205

Cov.:

AF XY:

0.290

AC XY:

210262

AN XY:

725646

show subpopulations

Gnomad4 AFR exome

AF:

0.525

Gnomad4 AMR exome

AF:

0.171

Gnomad4 ASJ exome

AF:

0.268

Gnomad4 EAS exome

AF:

0.453

Gnomad4 SAS exome

AF:

0.325

Gnomad4 FIN exome

AF:

0.340

Gnomad4 NFE exome

AF:

0.274

Gnomad4 OTH exome

AF:

0.307

GnomAD4 genome

AF:

0.352

AC:

53424

AN:

151926

Hom.:

10337

Cov.:

AF XY:

0.350

AC XY:

26005

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.516

Gnomad4 AMR

AF:

0.216

Gnomad4 ASJ

AF:

0.257

Gnomad4 EAS

AF:

0.424

Gnomad4 SAS

AF:

0.327

Gnomad4 FIN

AF:

0.333

Gnomad4 NFE

AF:

0.287

Gnomad4 OTH

AF:

0.332

Alfa

AF:

0.298

Hom.:

3060

Bravo

AF:

0.350

Asia WGS

AF:

0.387

AC:

1350

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

May 07, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

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

*15T>C in exon 20 of CCDC40: This variant is not expected to have clinical signi ficance because it has been identified in 49.7% (1929/3880) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs2304853). -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary ciliary dyskinesia 15

Benign:3

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 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. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:2

Jul 09, 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

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Glycogen storage disease, type II

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

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

-0.88

CADD

Benign

0.64

DANN

Benign

0.41

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