rs116824266

Variant names:

• chr17-80065493-C-T
• rs116824266
• NM_017950.4:c.1449C>T

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.1449C>T​(p.Thr483Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00264 in 1,613,072 control chromosomes in the GnomAD database, including 97 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (50 hom., cov: 29)
  • Exomes 𝑓: 0.0014 (47 hom.)
• Consequence: CCDC40 NM_017950.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.387
• Publications: 2 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

ENSG00000289689 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 17-80065493-C-T is Benign according to our data. Variant chr17-80065493-C-T is described in ClinVar as Benign. ClinVar VariationId is 226488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.387 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0503 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.1449C>T	p.Thr483Thr	synonymous	Exon 10 of 20	NP_060420.2
	CCDC40	NM_001243342.2		c.1449C>T	p.Thr483Thr	synonymous	Exon 10 of 18	NP_001230271.1
	CCDC40	NM_001330508.2		c.1449C>T	p.Thr483Thr	synonymous	Exon 10 of 11	NP_001317437.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC40	ENST00000397545.9	TSL:5 MANE Select	c.1449C>T	p.Thr483Thr	synonymous	Exon 10 of 20	ENSP00000380679.4
	CCDC40	ENST00000574799.5	TSL:1	n.986C>T		non_coding_transcript_exon	Exon 6 of 16
	CCDC40	ENST00000374876.4	TSL:1	c.1318-590C>T		intron	N/A	ENSP00000364010.4

Frequencies

GnomAD3 genomes AF: 0.0142 AC: 2165 AN: 152052 Hom.: 50 Cov.: 29

Gnomad AFR AF: 0.0495

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00537

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00958

GnomAD2 exomes AF: 0.00363 AC: 903 AN: 248486 AF XY: 0.00274

Gnomad AFR exome AF: 0.0533

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000800

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00143 AC: 2094 AN: 1460902 Hom.: 47 Cov.: 32 AF XY: 0.00122 AC XY: 888 AN XY: 726774

African (AFR) AF: 0.0523 AC: 1751 AN: 33480

American (AMR) AF: 0.00219 AC: 98 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52532

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.0000549 AC: 61 AN: 1111944

Other (OTH) AF: 0.00288 AC: 174 AN: 60386

GnomAD4 genome AF: 0.0142 AC: 2165 AN: 152170 Hom.: 50 Cov.: 29 AF XY: 0.0136 AC XY: 1008 AN XY: 74384

African (AFR) AF: 0.0493 AC: 2049 AN: 41520

American (AMR) AF: 0.00537 AC: 82 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5120

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68012

Other (OTH) AF: 0.00948 AC: 20 AN: 2110

Alfa AF: 0.00719 Hom.: 13

Bravo AF: 0.0161

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Thr483Thr in exon 10 of CCDC40: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 4.6% (194/4200) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs116824266).

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Primary ciliary dyskinesia Benign:2

Mar 09, 2017

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.

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 15 Benign:2

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.

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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	-0.70
CADD	Benign	0.061
DANN	Benign	0.75
PhyloP100		-0.39
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs116824266; hg19: chr17-78039292;