17-80048756-G-C

Variant names:

• chr17-80048756-G-C
• rs201042940
• NM_017950.4:c.850G>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_017950.4(CCDC40):​c.850G>C​(p.Asp284His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0024 in 1,608,890 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0016 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0025 (21 hom.)
• Consequence: CCDC40 NM_017950.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 0.526
• Publications: 11 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01399526).
• BP6: Variant 17-80048756-G-C is Benign according to our data. Variant chr17-80048756-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 260979.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0016 (244/152326) while in subpopulation SAS AF = 0.00871 (42/4824). AF 95% confidence interval is 0.00662. There are 3 homozygotes in GnomAd4. There are 132 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

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.850G>C	p.Asp284His	missense	Exon 5 of 20	NP_060420.2
	CCDC40	NM_001243342.2		c.850G>C	p.Asp284His	missense	Exon 5 of 18	NP_001230271.1
	CCDC40	NM_001330508.2		c.850G>C	p.Asp284His	missense	Exon 5 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.850G>C	p.Asp284His	missense	Exon 5 of 20	ENSP00000380679.4
	CCDC40	ENST00000374876.4	TSL:1	c.850G>C	p.Asp284His	missense	Exon 5 of 9	ENSP00000364010.4
	CCDC40	ENST00000574799.5	TSL:1	n.387G>C		non_coding_transcript_exon	Exon 1 of 16

Frequencies

GnomAD3 genomes AF: 0.00160 AC: 243 AN: 152208 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00829

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00209

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00283 AC: 666 AN: 235048 AF XY: 0.00336

Gnomad AFR exome AF: 0.000344

Gnomad AMR exome AF: 0.00103

Gnomad ASJ exome AF: 0.00541

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000994

Gnomad NFE exome AF: 0.00259

Gnomad OTH exome AF: 0.00379

GnomAD4 exome AF: 0.00248 AC: 3616 AN: 1456564 Hom.: 21 Cov.: 33 AF XY: 0.00271 AC XY: 1965 AN XY: 724066

African (AFR) AF: 0.00108 AC: 36 AN: 33404

American (AMR) AF: 0.00132 AC: 58 AN: 43792

Ashkenazi Jewish (ASJ) AF: 0.00622 AC: 162 AN: 26034

East Asian (EAS) AF: 0.00 AC: 0 AN: 39496

South Asian (SAS) AF: 0.00875 AC: 748 AN: 85504

European-Finnish (FIN) AF: 0.000227 AC: 12 AN: 52870

Middle Eastern (MID) AF: 0.0191 AC: 110 AN: 5764

European-Non Finnish (NFE) AF: 0.00207 AC: 2296 AN: 1109532

Other (OTH) AF: 0.00322 AC: 194 AN: 60168

GnomAD4 genome AF: 0.00160 AC: 244 AN: 152326 Hom.: 3 Cov.: 31 AF XY: 0.00177 AC XY: 132 AN XY: 74478

African (AFR) AF: 0.000409 AC: 17 AN: 41588

American (AMR) AF: 0.000785 AC: 12 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00871 AC: 42 AN: 4824

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10620

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00209 AC: 142 AN: 68030

Other (OTH) AF: 0.00427 AC: 9 AN: 2110

Alfa AF: 0.00242 Hom.: 1

Bravo AF: 0.00149

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000721 AC: 3

ESP6500EA AF: 0.00322 AC: 27

ExAC AF: 0.00281 AC: 340

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 20, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Asp284His in exon 5 of CCDC40: This variant is not expected to have clinical s ignificance because it has been identified in 1% (129/1262) of South Asian chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs201042940).

Primary ciliary dyskinesia Benign:2

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 15, 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

Mar 11, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 33574797)

Aug 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CCDC40: BP4, BS2

Male infertility Uncertain:1

MAGI's Lab - Research, MAGI Group

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Primary ciliary dyskinesia 15 Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.51	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.014	T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		0.53
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Benign	0.17
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.53
MVP		0.68
MPC		0.76
ClinPred		0.049	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.24
Mutation Taster		=98/2	polymorphism

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: rs201042940; hg19: chr17-78022555; COSMIC: COSV53898727; COSMIC: COSV53898727;