17-80097253-T-C

Variant names:

• chr17-80097253-T-C
• rs12952612
• NM_017950.4:c.3030T>C

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.3030T>C​(p.Asp1010Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.74 in 1,613,562 control chromosomes in the GnomAD database, including 444,182 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (39753 hom., cov: 32)
  • Exomes 𝑓: 0.74 (404429 hom.)
• Consequence: CCDC40 NM_017950.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.368
• Publications: 29 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=-0.76).
• BP6: Variant 17-80097253-T-C is Benign according to our data. Variant chr17-80097253-T-C is described in ClinVar as Benign. ClinVar VariationId is 178711.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.368 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.794 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.3030T>C	p.Asp1010Asp	synonymous	Exon 19 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.3030T>C	p.Asp1010Asp	synonymous	Exon 19 of 20	ENSP00000380679.4
	CCDC40	ENST00000574799.5	TSL:1	n.2567T>C		non_coding_transcript_exon	Exon 15 of 16
	CCDC40	ENST00000572253.5	TSL:2	n.3281T>C		non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes AF: 0.720 AC: 109475 AN: 151982 Hom.: 39737 Cov.: 32

Gnomad AFR AF: 0.691

Gnomad AMI AF: 0.649

Gnomad AMR AF: 0.590

Gnomad ASJ AF: 0.786

Gnomad EAS AF: 0.647

Gnomad SAS AF: 0.816

Gnomad FIN AF: 0.809

Gnomad MID AF: 0.851

Gnomad NFE AF: 0.750

Gnomad OTH AF: 0.707

GnomAD2 exomes AF: 0.722 AC: 180181 AN: 249404 AF XY: 0.738

Gnomad AFR exome AF: 0.693

Gnomad AMR exome AF: 0.517

Gnomad ASJ exome AF: 0.798

Gnomad EAS exome AF: 0.633

Gnomad FIN exome AF: 0.797

Gnomad NFE exome AF: 0.755

Gnomad OTH exome AF: 0.755

GnomAD4 exome AF: 0.742 AC: 1084848 AN: 1461462 Hom.: 404429 Cov.: 53 AF XY: 0.746 AC XY: 542238 AN XY: 727046

African (AFR) AF: 0.695 AC: 23279 AN: 33476

American (AMR) AF: 0.528 AC: 23599 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.800 AC: 20918 AN: 26136

East Asian (EAS) AF: 0.696 AC: 27620 AN: 39696

South Asian (SAS) AF: 0.814 AC: 70180 AN: 86256

European-Finnish (FIN) AF: 0.797 AC: 42360 AN: 53168

Middle Eastern (MID) AF: 0.818 AC: 4721 AN: 5768

European-Non Finnish (NFE) AF: 0.744 AC: 826956 AN: 1111850

Other (OTH) AF: 0.749 AC: 45215 AN: 60390

GnomAD4 genome AF: 0.720 AC: 109530 AN: 152100 Hom.: 39753 Cov.: 32 AF XY: 0.719 AC XY: 53476 AN XY: 74366

African (AFR) AF: 0.690 AC: 28634 AN: 41480

American (AMR) AF: 0.589 AC: 9008 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.786 AC: 2729 AN: 3472

East Asian (EAS) AF: 0.647 AC: 3349 AN: 5176

South Asian (SAS) AF: 0.816 AC: 3931 AN: 4820

European-Finnish (FIN) AF: 0.809 AC: 8571 AN: 10600

Middle Eastern (MID) AF: 0.861 AC: 253 AN: 294

European-Non Finnish (NFE) AF: 0.750 AC: 50973 AN: 67948

Other (OTH) AF: 0.707 AC: 1491 AN: 2110

Alfa AF: 0.740 Hom.: 86886

Bravo AF: 0.702

Asia WGS AF: 0.732 AC: 2547 AN: 3478

EpiCase AF: 0.752

EpiControl AF: 0.754

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Asp1010Asp in exon 19 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 29.2% (1182/4046) of African American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs12952612).

PreventionGenetics, part of Exact Sciences

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

Primary ciliary dyskinesia Benign:3

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.

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

Primary ciliary dyskinesia 15 Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 12, 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	-0.76
CADD	Benign	1.7
DANN	Benign	0.26
PhyloP100		-0.37
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs12952612; hg19: chr17-78071052; COSMIC: COSV56408680; COSMIC: COSV56408680;