17-80099763-A-G

Variant names:

• chr17-80099763-A-G
• rs2304854
• NM_017950.4:c.3417A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_017950.4(CCDC40):​c.3417A>G​(p.Pro1139Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.458 in 1,612,434 control chromosomes in the GnomAD database, including 171,762 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (18977 hom., cov: 31)
  • Exomes 𝑓: 0.45 (152785 hom.)
• Consequence: CCDC40 NM_017950.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -1.08
• Publications: 25 publications found

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 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 15

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, Laboratory for Molecular Medicine
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autoimmune disease

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 17-80099763-A-G is Benign according to our data. Variant chr17-80099763-A-G is described in ClinVar as Benign. ClinVar VariationId is 178712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.09 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.599 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017950.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC40	NM_017950.4	MANE Select	c.3417A>G	p.Pro1139Pro	synonymous	Exon 20 of 20	NP_060420.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC40	ENST00000397545.9	TSL:5 MANE Select	c.3417A>G	p.Pro1139Pro	synonymous	Exon 20 of 20	ENSP00000380679.4
	CCDC40	ENST00000574799.5	TSL:1	n.2954A>G		non_coding_transcript_exon	Exon 16 of 16

Frequencies

GnomAD3 genomes AF: 0.492 AC: 74666 AN: 151786 Hom.: 18954 Cov.: 31

Gnomad AFR AF: 0.605

Gnomad AMI AF: 0.437

Gnomad AMR AF: 0.332

Gnomad ASJ AF: 0.486

Gnomad EAS AF: 0.425

Gnomad SAS AF: 0.511

Gnomad FIN AF: 0.542

Gnomad MID AF: 0.596

Gnomad NFE AF: 0.457

Gnomad OTH AF: 0.466

GnomAD2 exomes AF: 0.451 AC: 111378 AN: 247100 AF XY: 0.461

Gnomad AFR exome AF: 0.610

Gnomad AMR exome AF: 0.237

Gnomad ASJ exome AF: 0.499

Gnomad EAS exome AF: 0.410

Gnomad FIN exome AF: 0.536

Gnomad NFE exome AF: 0.460

Gnomad OTH exome AF: 0.475

GnomAD4 exome AF: 0.454 AC: 662967 AN: 1460530 Hom.: 152785 Cov.: 50 AF XY: 0.457 AC XY: 331983 AN XY: 726564

African (AFR) AF: 0.615 AC: 20587 AN: 33468

American (AMR) AF: 0.253 AC: 11284 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 13049 AN: 26112

East Asian (EAS) AF: 0.454 AC: 18015 AN: 39684

South Asian (SAS) AF: 0.513 AC: 44213 AN: 86238

European-Finnish (FIN) AF: 0.542 AC: 28462 AN: 52554

Middle Eastern (MID) AF: 0.545 AC: 3141 AN: 5764

European-Non Finnish (NFE) AF: 0.446 AC: 495963 AN: 1111674

Other (OTH) AF: 0.468 AC: 28253 AN: 60364

GnomAD4 genome AF: 0.492 AC: 74734 AN: 151904 Hom.: 18977 Cov.: 31 AF XY: 0.491 AC XY: 36484 AN XY: 74242

African (AFR) AF: 0.605 AC: 25056 AN: 41424

American (AMR) AF: 0.331 AC: 5064 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.486 AC: 1684 AN: 3468

East Asian (EAS) AF: 0.425 AC: 2179 AN: 5130

South Asian (SAS) AF: 0.511 AC: 2468 AN: 4826

European-Finnish (FIN) AF: 0.542 AC: 5731 AN: 10580

Middle Eastern (MID) AF: 0.599 AC: 175 AN: 292

European-Non Finnish (NFE) AF: 0.457 AC: 30990 AN: 67878

Other (OTH) AF: 0.469 AC: 989 AN: 2110

Alfa AF: 0.460 Hom.: 42299

Bravo AF: 0.479

EpiCase AF: 0.454

EpiControl AF: 0.453

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 07, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Pro1139Pro in exon 20 of CCDC40: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 44.7% (3724/8334) of European American chromosomes from a broad population by the NHLBI Exome Seq uencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2304854).

Primary ciliary dyskinesia Benign:3

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 07, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Primary ciliary dyskinesia 15 Benign:3

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Glycogen storage disease, type II Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.060
DANN	Benign	0.34
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2304854; hg19: chr17-78073562; COSMIC: COSV56409368; COSMIC: COSV56409368;