17-80040225-G-A

Position:

• chr17-80040225-G-A

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.507G>A​(p.Ser169=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,613,862 control chromosomes in the GnomAD database, including 1,261 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (632 hom., cov: 32)
  • Exomes 𝑓: 0.0082 (629 hom.)
• Consequence: CCDC40 NM_017950.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.70

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 17-80040225-G-A is Benign according to our data. Variant chr17-80040225-G-A is described in ClinVar as [Benign]. Clinvar id is 162845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80040225-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.7 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.165 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC40	NM_017950.4	c.507G>A	p.Ser169=	synonymous_variant	3/20	ENST00000397545.9	NP_060420.2
CCDC40	NM_001243342.2	c.507G>A	p.Ser169=	synonymous_variant	3/18		NP_001230271.1
CCDC40	NM_001330508.2	c.507G>A	p.Ser169=	synonymous_variant	3/11		NP_001317437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC40	ENST00000397545.9	c.507G>A	p.Ser169=	synonymous_variant	3/20	5	NM_017950.4	ENSP00000380679	P2

Frequencies

GnomAD3 genomes AF: 0.0501 AC: 7629 AN: 152160 Hom.: 623 Cov.: 32

Gnomad AFR AF: 0.167

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0183

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0412

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00134

Gnomad OTH AF: 0.0359

GnomAD3 exomes AF: 0.0187 AC: 4643 AN: 247948 Hom.: 267 AF XY: 0.0173 AC XY: 2337 AN XY: 134792

Gnomad AFR exome AF: 0.173

Gnomad AMR exome AF: 0.0109

Gnomad ASJ exome AF: 0.00838

Gnomad EAS exome AF: 0.00111

Gnomad SAS exome AF: 0.0421

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00144

Gnomad OTH exome AF: 0.00993

GnomAD4 exome AF: 0.00824 AC: 12050 AN: 1461584 Hom.: 629 Cov.: 33 AF XY: 0.00869 AC XY: 6316 AN XY: 727082

Gnomad4 AFR exome AF: 0.171

Gnomad4 AMR exome AF: 0.0116

Gnomad4 ASJ exome AF: 0.00697

Gnomad4 EAS exome AF: 0.00169

Gnomad4 SAS exome AF: 0.0390

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.000962

Gnomad4 OTH exome AF: 0.0170

GnomAD4 genome AF: 0.0504 AC: 7677 AN: 152278 Hom.: 632 Cov.: 32 AF XY: 0.0490 AC XY: 3647 AN XY: 74474

Gnomad4 AFR AF: 0.168

Gnomad4 AMR AF: 0.0183

Gnomad4 ASJ AF: 0.00893

Gnomad4 EAS AF: 0.00173

Gnomad4 SAS AF: 0.0412

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00134

Gnomad4 OTH AF: 0.0360

Alfa AF: 0.0209 Hom.: 127

Bravo AF: 0.0558

Asia WGS AF: 0.0430 AC: 150 AN: 3478

EpiCase AF: 0.00169

EpiControl AF: 0.00237

ClinVar

Significance: Benign

Submissions summary: Benign:7

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	Ser169Ser in exon 3 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 15.5% (614/3952) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2885349). -

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -

Primary ciliary dyskinesia 15 Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.96
DANN	Benign	0.44

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: rs2885349; hg19: chr17-78014024;