17-80081959-T-G

Position:

• chr17-80081959-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_017950.4(CCDC40):​c.1890T>G​(p.Ala630Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.509 in 1,613,186 control chromosomes in the GnomAD database, including 212,252 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (20864 hom., cov: 30)
  • Exomes 𝑓: 0.51 (191388 hom.)
• Consequence: CCDC40 NM_017950.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -2.81

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 17-80081959-T-G is Benign according to our data. Variant chr17-80081959-T-G is described in ClinVar as [Benign]. Clinvar id is 162850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80081959-T-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.81 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.582 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC40	NM_017950.4	c.1890T>G	p.Ala630Ala	synonymous_variant	12/20	ENST00000397545.9	NP_060420.2
CCDC40	NM_001243342.2	c.1890T>G	p.Ala630Ala	synonymous_variant	12/18		NP_001230271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC40	ENST00000397545.9	c.1890T>G	p.Ala630Ala	synonymous_variant	12/20	5	NM_017950.4	ENSP00000380679.4
CCDC40	ENST00000574799.5	n.1427T>G		non_coding_transcript_exon_variant	8/16	1
CCDC40	ENST00000374877.7	c.1890T>G	p.Ala630Ala	synonymous_variant	12/18	5		ENSP00000364011.3
CCDC40	ENST00000572253.5	n.517T>G		non_coding_transcript_exon_variant	1/6	2

Frequencies

GnomAD3 genomes AF: 0.519 AC: 78617 AN: 151548 Hom.: 20865 Cov.: 30

Gnomad AFR AF: 0.589

Gnomad AMI AF: 0.326

Gnomad AMR AF: 0.429

Gnomad ASJ AF: 0.607

Gnomad EAS AF: 0.278

Gnomad SAS AF: 0.432

Gnomad FIN AF: 0.486

Gnomad MID AF: 0.650

Gnomad NFE AF: 0.522

Gnomad OTH AF: 0.548

GnomAD3 exomes AF: 0.481 AC: 119687 AN: 248586 Hom.: 29752 AF XY: 0.487 AC XY: 65742 AN XY: 134944

Gnomad AFR exome AF: 0.589

Gnomad AMR exome AF: 0.384

Gnomad ASJ exome AF: 0.603

Gnomad EAS exome AF: 0.272

Gnomad SAS exome AF: 0.453

Gnomad FIN exome AF: 0.489

Gnomad NFE exome AF: 0.523

Gnomad OTH exome AF: 0.519

GnomAD4 exome AF: 0.508 AC: 743079 AN: 1461518 Hom.: 191388 Cov.: 45 AF XY: 0.508 AC XY: 369258 AN XY: 727056

Gnomad4 AFR exome AF: 0.595

Gnomad4 AMR exome AF: 0.392

Gnomad4 ASJ exome AF: 0.603

Gnomad4 EAS exome AF: 0.310

Gnomad4 SAS exome AF: 0.453

Gnomad4 FIN exome AF: 0.490

Gnomad4 NFE exome AF: 0.519

Gnomad4 OTH exome AF: 0.520

GnomAD4 genome AF: 0.519 AC: 78647 AN: 151668 Hom.: 20864 Cov.: 30 AF XY: 0.512 AC XY: 37967 AN XY: 74106

Gnomad4 AFR AF: 0.588

Gnomad4 AMR AF: 0.428

Gnomad4 ASJ AF: 0.607

Gnomad4 EAS AF: 0.279

Gnomad4 SAS AF: 0.430

Gnomad4 FIN AF: 0.486

Gnomad4 NFE AF: 0.522

Gnomad4 OTH AF: 0.543

Alfa AF: 0.517 Hom.: 13237

Bravo AF: 0.518

Asia WGS AF: 0.339 AC: 1184 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

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, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Ala630Ala in exon 12 of CCDC40: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 49.0% (4178/8520) of European American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs35578653). -

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:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 07, 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	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.30
DANN	Benign	0.34

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: rs35578653; hg19: chr17-78055758; COSMIC: COSV66474806;