rs7212525

Positions:

• chr17-80047415-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017950.4(CCDC40):​c.676+13T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.249 in 1,607,888 control chromosomes in the GnomAD database, including 56,670 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (11318 hom., cov: 32)
  • Exomes 𝑓: 0.24 (45352 hom.)
• Consequence: CCDC40 NM_017950.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.10

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 17-80047415-T-C is Benign according to our data. Variant chr17-80047415-T-C is described in ClinVar as [Benign]. Clinvar id is 178707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80047415-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.621 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC40	NM_017950.4	c.676+13T>C		intron_variant		ENST00000397545.9
CCDC40	NM_001243342.2	c.676+13T>C		intron_variant
CCDC40	NM_001330508.2	c.676+13T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC40	ENST00000397545.9	c.676+13T>C		intron_variant		5	NM_017950.4	P2
	ENST00000695611.1			downstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.339 AC: 51547 AN: 151974 Hom.: 11296 Cov.: 32

Gnomad AFR AF: 0.627

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.165

Gnomad SAS AF: 0.237

Gnomad FIN AF: 0.275

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.238

Gnomad OTH AF: 0.303

GnomAD3 exomes AF: 0.246 AC: 58669 AN: 238144 Hom.: 8742 AF XY: 0.247 AC XY: 32036 AN XY: 129908

Gnomad AFR exome AF: 0.640

Gnomad AMR exome AF: 0.132

Gnomad ASJ exome AF: 0.237

Gnomad EAS exome AF: 0.162

Gnomad SAS exome AF: 0.260

Gnomad FIN exome AF: 0.278

Gnomad NFE exome AF: 0.234

Gnomad OTH exome AF: 0.250

GnomAD4 exome AF: 0.240 AC: 349238 AN: 1455796 Hom.: 45352 Cov.: 34 AF XY: 0.240 AC XY: 173865 AN XY: 723964

Gnomad4 AFR exome AF: 0.635

Gnomad4 AMR exome AF: 0.141

Gnomad4 ASJ exome AF: 0.230

Gnomad4 EAS exome AF: 0.182

Gnomad4 SAS exome AF: 0.255

Gnomad4 FIN exome AF: 0.284

Gnomad4 NFE exome AF: 0.230

Gnomad4 OTH exome AF: 0.251

GnomAD4 genome AF: 0.339 AC: 51621 AN: 152092 Hom.: 11318 Cov.: 32 AF XY: 0.336 AC XY: 25026 AN XY: 74372

Gnomad4 AFR AF: 0.628

Gnomad4 AMR AF: 0.188

Gnomad4 ASJ AF: 0.237

Gnomad4 EAS AF: 0.165

Gnomad4 SAS AF: 0.237

Gnomad4 FIN AF: 0.275

Gnomad4 NFE AF: 0.238

Gnomad4 OTH AF: 0.302

Alfa AF: 0.290 Hom.: 1429

Bravo AF: 0.343

Asia WGS AF: 0.233 AC: 814 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

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	676+13T>C in intron 4 of CCDC40: This variant is not expected to have clinical s ignificance because it is not located within the conserved splice consensus sequ ence. It has been identified in 40.2% (1665/4138) of African American chromosome s from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.w ashington.edu/EVS; dbSNP rs7212525). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Primary ciliary dyskinesia 15 Benign:3

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, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Primary ciliary dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.67
DANN	Benign	0.17
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Other links and lift over

dbSNP: rs7212525; hg19: chr17-78021214;