17-80099790-T-C

Variant names:

• chr17-80099790-T-C
• rs2304853
• ENST00000574799.5:n.2981T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000574799.5(CCDC40):​n.2981T>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.294 in 1,610,396 control chromosomes in the GnomAD database, including 73,542 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (10337 hom., cov: 32)
  • Exomes 𝑓: 0.29 (63205 hom.)
• Consequence: CCDC40 ENST00000574799.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.649
• Publications: 13 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 17-80099790-T-C is Benign according to our data. Variant chr17-80099790-T-C is described in ClinVar as Benign. ClinVar VariationId is 162853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.511 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000574799.5. 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.*15T>C		3_prime_UTR	Exon 20 of 20	NP_060420.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC40	ENST00000574799.5	TSL:1	n.2981T>C		non_coding_transcript_exon	Exon 16 of 16
	CCDC40	ENST00000397545.9	TSL:5 MANE Select	c.*15T>C		3_prime_UTR	Exon 20 of 20	ENSP00000380679.4

Frequencies

GnomAD3 genomes AF: 0.352 AC: 53366 AN: 151808 Hom.: 10320 Cov.: 32

Gnomad AFR AF: 0.517

Gnomad AMI AF: 0.337

Gnomad AMR AF: 0.216

Gnomad ASJ AF: 0.257

Gnomad EAS AF: 0.424

Gnomad SAS AF: 0.326

Gnomad FIN AF: 0.333

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.287

Gnomad OTH AF: 0.328

GnomAD2 exomes AF: 0.302 AC: 73977 AN: 245030 AF XY: 0.305

Gnomad AFR exome AF: 0.521

Gnomad AMR exome AF: 0.159

Gnomad ASJ exome AF: 0.266

Gnomad EAS exome AF: 0.409

Gnomad FIN exome AF: 0.329

Gnomad NFE exome AF: 0.289

Gnomad OTH exome AF: 0.309

GnomAD4 exome AF: 0.288 AC: 420697 AN: 1458470 Hom.: 63205 Cov.: 35 AF XY: 0.290 AC XY: 210262 AN XY: 725646

African (AFR) AF: 0.525 AC: 17556 AN: 33416

American (AMR) AF: 0.171 AC: 7624 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.268 AC: 6984 AN: 26094

East Asian (EAS) AF: 0.453 AC: 17967 AN: 39664

South Asian (SAS) AF: 0.325 AC: 28004 AN: 86184

European-Finnish (FIN) AF: 0.340 AC: 17527 AN: 51604

Middle Eastern (MID) AF: 0.302 AC: 1743 AN: 5764

European-Non Finnish (NFE) AF: 0.274 AC: 304774 AN: 1110800

Other (OTH) AF: 0.307 AC: 18518 AN: 60308

GnomAD4 genome AF: 0.352 AC: 53424 AN: 151926 Hom.: 10337 Cov.: 32 AF XY: 0.350 AC XY: 26005 AN XY: 74278

African (AFR) AF: 0.516 AC: 21370 AN: 41384

American (AMR) AF: 0.216 AC: 3294 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.257 AC: 889 AN: 3462

East Asian (EAS) AF: 0.424 AC: 2185 AN: 5150

South Asian (SAS) AF: 0.327 AC: 1579 AN: 4824

European-Finnish (FIN) AF: 0.333 AC: 3526 AN: 10574

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.287 AC: 19467 AN: 67940

Other (OTH) AF: 0.332 AC: 699 AN: 2108

Alfa AF: 0.303 Hom.: 3763

Bravo AF: 0.350

Asia WGS AF: 0.387 AC: 1350 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

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

*15T>C in exon 20 of CCDC40: This variant is not expected to have clinical signi ficance because it has been identified in 49.7% (1929/3880) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs2304853).

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

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Primary ciliary dyskinesia Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

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	-0.88
CADD	Benign	0.64
DANN	Benign	0.41
PhyloP100		-0.65
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: rs2304853; hg19: chr17-78073589; COSMIC: COSV56408051; COSMIC: COSV56408051;