rs2289533

chr17-80050295-C-T

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.1159+12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.237 in 1,548,256 control chromosomes in the GnomAD database, including 45,677 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3592 hom., cov: 32)
  • Exomes 𝑓: 0.24 (42085 hom.)
• Consequence: CCDC40 NM_017950.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.684

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=-0.8).
• BP6: Variant 17-80050295-C-T is Benign according to our data. Variant chr17-80050295-C-T is described in ClinVar as [Benign]. Clinvar id is 162847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80050295-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.36 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC40	NM_017950.4	c.1159+12C>T		intron_variant		ENST00000397545.9
CCDC40	NM_001243342.2	c.1159+12C>T		intron_variant
CCDC40	NM_001330508.2	c.1159+12C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC40	ENST00000397545.9	c.1159+12C>T		intron_variant		5	NM_017950.4	P2
	ENST00000695611.1	n.1432-2776G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29749 AN: 152010 Hom.: 3587 Cov.: 32

Gnomad AFR AF: 0.0540

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.292

Gnomad ASJ AF: 0.188

Gnomad EAS AF: 0.373

Gnomad SAS AF: 0.210

Gnomad FIN AF: 0.218

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.201

GnomAD3 exomes AF: 0.242 AC: 37159 AN: 153680 Hom.: 4956 AF XY: 0.238 AC XY: 19533 AN XY: 82190

Gnomad AFR exome AF: 0.0427

Gnomad AMR exome AF: 0.303

Gnomad ASJ exome AF: 0.183

Gnomad EAS exome AF: 0.402

Gnomad SAS exome AF: 0.202

Gnomad FIN exome AF: 0.216

Gnomad NFE exome AF: 0.245

Gnomad OTH exome AF: 0.214

GnomAD4 exome AF: 0.241 AC: 337160 AN: 1396128 Hom.: 42085 Cov.: 33 AF XY: 0.241 AC XY: 166177 AN XY: 689096

Gnomad4 AFR exome AF: 0.0415

Gnomad4 AMR exome AF: 0.301

Gnomad4 ASJ exome AF: 0.184

Gnomad4 EAS exome AF: 0.318

Gnomad4 SAS exome AF: 0.207

Gnomad4 FIN exome AF: 0.221

Gnomad4 NFE exome AF: 0.249

Gnomad4 OTH exome AF: 0.229

GnomAD4 genome AF: 0.196 AC: 29769 AN: 152128 Hom.: 3592 Cov.: 32 AF XY: 0.199 AC XY: 14781 AN XY: 74352

Gnomad4 AFR AF: 0.0539

Gnomad4 AMR AF: 0.293

Gnomad4 ASJ AF: 0.188

Gnomad4 EAS AF: 0.373

Gnomad4 SAS AF: 0.212

Gnomad4 FIN AF: 0.218

Gnomad4 NFE AF: 0.242

Gnomad4 OTH AF: 0.203

Alfa AF: 0.235 Hom.: 7698

Bravo AF: 0.194

Asia WGS AF: 0.290 AC: 1007 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	1159+12C>T in intron 7 of CCDC40: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus seq uence. It has been identified in 21.4% (1740/8114) of European American chromoso mes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs .washington.edu/EVS; dbSNP rs2289533). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Primary ciliary dyskinesia 15 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	-	- -

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	-0.80
Cadd	Benign	6.0
Dann	Benign	0.67

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: rs2289533; hg19: chr17-78024094;