rs61734950

chr17-80058878-C-T

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.1338C>T(p.Leu446=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 1,614,056 control chromosomes in the GnomAD database, including 1,082 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.044 (487 hom., cov: 32)
  • Exomes 𝑓: 0.0076 (595 hom.)
• Consequence: CCDC40 NM_017950.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.905

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 17-80058878-C-T is Benign according to our data. Variant chr17-80058878-C-T is described in ClinVar as [Benign]. Clinvar id is 162848.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80058878-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.905 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.146 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC40	NM_017950.4	c.1338C>T	p.Leu446=	synonymous_variant	9/20	ENST00000397545.9
LOC124904074	XR_007065931.1	n.913G>A		non_coding_transcript_exon_variant	2/2
CCDC40	NM_001243342.2	c.1338C>T	p.Leu446=	synonymous_variant	9/18
CCDC40	NM_001330508.2	c.1338C>T	p.Leu446=	synonymous_variant	9/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC40	ENST00000397545.9	c.1338C>T	p.Leu446=	synonymous_variant	9/20	5	NM_017950.4	P2
	ENST00000695611.1	n.921G>A		non_coding_transcript_exon_variant	2/3

Frequencies

GnomAD3 genomes AF: 0.0441 AC: 6705 AN: 152050 Hom.: 480 Cov.: 32

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0127

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0518

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000618

Gnomad OTH AF: 0.0315

GnomAD3 exomes AF: 0.0176 AC: 4403 AN: 249580 Hom.: 263 AF XY: 0.0172 AC XY: 2323 AN XY: 135406

Gnomad AFR exome AF: 0.155

Gnomad AMR exome AF: 0.00724

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.000445

Gnomad SAS exome AF: 0.0533

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000503

Gnomad OTH exome AF: 0.00808

GnomAD4 exome AF: 0.00763 AC: 11155 AN: 1461888 Hom.: 595 Cov.: 32 AF XY: 0.00839 AC XY: 6101 AN XY: 727248

Gnomad4 AFR exome AF: 0.153

Gnomad4 AMR exome AF: 0.00812

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.000327

Gnomad4 SAS exome AF: 0.0500

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000388

Gnomad4 OTH exome AF: 0.0144

GnomAD4 genome AF: 0.0443 AC: 6745 AN: 152168 Hom.: 487 Cov.: 32 AF XY: 0.0437 AC XY: 3249 AN XY: 74416

Gnomad4 AFR AF: 0.149

Gnomad4 AMR AF: 0.0127

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0524

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000618

Gnomad4 OTH AF: 0.0317

Alfa AF: 0.0172 Hom.: 108

Bravo AF: 0.0488

Asia WGS AF: 0.0440 AC: 153 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.000771

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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	Leu446Leu in exon 9 of CCDC40: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 13.8% (578/4178) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs61734950). -

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 30, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

- -

Primary ciliary dyskinesia 15 Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
Cadd	Benign	9.2
Dann	Benign	0.50
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7

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: rs61734950; hg19: chr17-78032677;