NM_017950.4:c.334A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_017950.4(CCDC40):c.334A>G(p.Thr112Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00397 in 1,614,104 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T112M) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0025 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0041 ( 16 hom. )

Consequence

CCDC40
NM_017950.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: -0.981

Publications

6 publications found

Variant links:

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

CCDC40 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0055594146).

BP6

Variant 17-80040052-A-G is Benign according to our data. Variant chr17-80040052-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 166808.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00249 (379/152342) while in subpopulation NFE AF = 0.00406 (276/68026). AF 95% confidence interval is 0.00366. There are 0 homozygotes in GnomAd4. There are 177 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 16 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC40	NM_017950.4 link	c.334A>G	p.Thr112Ala	missense_variant	Exon 3 of 20	ENST00000397545.9	NP_060420.2	Q4G0X9-1
CCDC40	NM_001243342.2 link	c.334A>G	p.Thr112Ala	missense_variant	Exon 3 of 18		NP_001230271.1	Q4G0X9-2
CCDC40	NM_001330508.2 link	c.334A>G	p.Thr112Ala	missense_variant	Exon 3 of 11		NP_001317437.1	Q4G0X9-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC40	ENST00000397545.9 link	c.334A>G	p.Thr112Ala	missense_variant	Exon 3 of 20	5	NM_017950.4	ENSP00000380679.4		Q4G0X9-1

Frequencies

GnomAD3 genomes

AF:

0.00248

AC:

378

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000892

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00249

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00406

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00236

AC:

585

AN:

248092

AF XY:

0.00250

show subpopulations

Gnomad AFR exome

AF:

0.000387

Gnomad AMR exome

AF:

0.00136

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000510

Gnomad NFE exome

AF:

0.00381

Gnomad OTH exome

AF:

0.00281

GnomAD4 exome

AF:

0.00413

AC:

6036

AN:

1461762

Hom.:

Cov.:

AF XY:

0.00399

AC XY:

2900

AN XY:

727212

show subpopulations

African (AFR)

AF:

0.000568

AC:

AN:

33474

American (AMR)

AF:

0.00161

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00249

AC:

215

AN:

86258

European-Finnish (FIN)

AF:

0.000805

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00487

AC:

5416

AN:

1111892

Other (OTH)

AF:

0.00432

AC:

261

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

304

609

913

1218

1522

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

214

428

642

856

1070

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00249

AC:

379

AN:

152342

Hom.:

Cov.:

AF XY:

0.00238

AC XY:

177

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.000890

AC:

AN:

41584

American (AMR)

AF:

0.00248

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00248

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000941

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00406

AC:

276

AN:

68026

Other (OTH)

AF:

0.00237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00346

Hom.:

Bravo

AF:

0.00238

TwinsUK

AF:

0.00620

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000770

AC:

ESP6500EA

AF:

0.00362

AC:

ExAC

AF:

0.00232

AC:

280

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00420

EpiControl

AF:

0.00302

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 15

Uncertain:1Benign:1

Nov 09, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

not specified

Benign:2

Jul 12, 2016

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 06, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Thr112Ala in exon 3 of CCDC40: This variant is not expected to have clinical s ignificance because it has been identified in 0.3% (200/66682) of European chrom osomes, including 3 homozygotes, by the Exome Aggregation Consortium (ExAC, http ://exac.broadinstitute.org; dbSNP rs201709592). -

Primary ciliary dyskinesia

Benign:2

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 20, 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:1

Jun 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CCDC40: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.58

CADD

Benign

0.29

(source)

DANN

Benign

0.55

DEOGEN2

Benign

0.027

.;T;.;.;.;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0063

LIST_S2

Benign

0.50

T;T;T;T;T;T

M_CAP

Benign

0.0015

MetaRNN

Benign

0.0056

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

N;N;N;N;.;.

PhyloP100

-0.98

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.45

N;N;N;N;.;.

REVEL

Benign

0.017

Sift

Benign

0.68

T;T;T;T;.;.

Sift4G

Benign

0.89

T;T;T;T;D;T

Polyphen

0.0030, 0.015

.;B;.;B;.;.

Vest4

0.035

MVP

0.040

MPC

0.17

ClinPred

0.0011

GERP RS

-5.5

Varity_R

0.019

gMVP

0.12

Mutation Taster

=99/1

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over