rs61740509

Variant names:

• chr17-80099686-G-A
• rs61740509
• NM_017950.4:c.3340G>A

Variant summary

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

The NM_017950.4(CCDC40):​c.3340G>A​(p.Val1114Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00599 in 1,613,850 control chromosomes in the GnomAD database, including 218 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (20 hom., cov: 32)
  • Exomes 𝑓: 0.0057 (198 hom.)
• Consequence: CCDC40 NM_017950.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.759
• Publications: 10 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 (MetaRNN=0.002135545).
• BP6: Variant 17-80099686-G-A is Benign according to our data. Variant chr17-80099686-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95880.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0782 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.3340G>A	p.Val1114Met	missense	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.3340G>A	p.Val1114Met	missense	Exon 20 of 20	ENSP00000380679.4
	CCDC40	ENST00000574799.5	TSL:1	n.2877G>A		non_coding_transcript_exon	Exon 16 of 16

Frequencies

GnomAD3 genomes AF: 0.00839 AC: 1277 AN: 152152 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0509

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.0146

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00341

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.0148 AC: 3696 AN: 249158 AF XY: 0.0115

Gnomad AFR exome AF: 0.000841

Gnomad AMR exome AF: 0.0832

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0129

Gnomad NFE exome AF: 0.00291

Gnomad OTH exome AF: 0.00941

GnomAD4 exome AF: 0.00574 AC: 8391 AN: 1461580 Hom.: 198 Cov.: 36 AF XY: 0.00536 AC XY: 3895 AN XY: 727074

African (AFR) AF: 0.000836 AC: 28 AN: 33480

American (AMR) AF: 0.0804 AC: 3594 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00508 AC: 438 AN: 86258

European-Finnish (FIN) AF: 0.0119 AC: 632 AN: 53122

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5768

European-Non Finnish (NFE) AF: 0.00301 AC: 3350 AN: 1112002

Other (OTH) AF: 0.00550 AC: 332 AN: 60392

GnomAD4 genome AF: 0.00840 AC: 1279 AN: 152270 Hom.: 20 Cov.: 32 AF XY: 0.0101 AC XY: 755 AN XY: 74452

African (AFR) AF: 0.00142 AC: 59 AN: 41550

American (AMR) AF: 0.0508 AC: 778 AN: 15300

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

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.00539 AC: 26 AN: 4826

European-Finnish (FIN) AF: 0.0146 AC: 155 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00341 AC: 232 AN: 68014

Other (OTH) AF: 0.0128 AC: 27 AN: 2112

Alfa AF: 0.00421 Hom.: 15

Bravo AF: 0.0112

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.00121 AC: 5

ESP6500EA AF: 0.00238 AC: 20

ExAC AF: 0.0118 AC: 1433

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.00349

EpiControl AF: 0.00273

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 01, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

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

Val1114Met in exon 20 of CCDC40: This variant is not expected to have clinical s ignificance because it has been identified in 10.8% (13/120) of Colombian chromo somes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.n ih.gov/projects/SNP; dbSNP rs61740509).

Primary ciliary dyskinesia Benign:3

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 23, 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.

not provided Benign:2

Jul 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Glycogen storage disease, type II Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Primary ciliary dyskinesia 15 Benign:1

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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.091	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.76
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.19
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.022	D
Polyphen		0.99	D
Vest4		0.14
MPC		0.60
ClinPred		0.012	T
GERP RS		2.4
Varity_R		0.074
gMVP		0.20
Mutation Taster		=98/2	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: rs61740509; hg19: chr17-78073485; COSMIC: COSV56409883; COSMIC: COSV56409883;