17-80095398-G-A

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.2968G>A(p.Asp990Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00068 in 1,614,132 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00072 ( 1 hom., cov: 34)

Exomes 𝑓: 0.00068 ( 4 hom. )

Consequence

CCDC40
NM_017950.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 1.79

Publications

8 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: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Ambry Genetics, 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=0.011015624).

BP6

Variant 17-80095398-G-A is Benign according to our data. Variant chr17-80095398-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 288542.

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.000676 (988/1461756) while in subpopulation EAS AF = 0.00438 (174/39700). AF 95% confidence interval is 0.00385. There are 4 homozygotes in GnomAdExome4. There are 552 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC40	NM_017950.4	MANE Select	c.2968G>A	p.Asp990Asn	missense	Exon 18 of 20	NP_060420.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CCDC40	ENST00000397545.9	TSL:5 MANE Select	c.2968G>A	p.Asp990Asn	missense	Exon 18 of 20	ENSP00000380679.4	Q4G0X9-1
CCDC40	ENST00000574799.5	TSL:1	n.2505G>A		non_coding_transcript_exon	Exon 14 of 16
CCDC40	ENST00000897784.1		c.3160G>A	p.Asp1054Asn	missense	Exon 19 of 21	ENSP00000567843.1

Frequencies

GnomAD3 genomes

AF:

0.000722

AC:

110

AN:

152258

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00385

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000661

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00125

AC:

311

AN:

248752

AF XY:

0.00133

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00317

Gnomad FIN exome

AF:

0.00316

Gnomad NFE exome

AF:

0.00123

Gnomad OTH exome

AF:

0.00165

GnomAD4 exome

AF:

0.000676

AC:

988

AN:

1461756

Hom.:

Cov.:

AF XY:

0.000759

AC XY:

552

AN XY:

727176

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00438

AC:

174

AN:

39700

South Asian (SAS)

AF:

0.00112

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00330

AC:

176

AN:

53300

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000423

AC:

470

AN:

1112006

Other (OTH)

AF:

0.00109

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

122

182

243

304

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000715

AC:

109

AN:

152376

Hom.:

Cov.:

AF XY:

0.000899

AC XY:

AN XY:

74522

show subpopulations

African (AFR)

AF:

0.0000240

AC:

AN:

41594

American (AMR)

AF:

0.000196

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00386

AC:

AN:

5188

South Asian (SAS)

AF:

0.00166

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00282

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000661

AC:

AN:

68038

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000987

Hom.:

Bravo

AF:

0.000363

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000235

AC:

ExAC

AF:

0.00158

AC:

191

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000533

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Primary ciliary dyskinesia (2)

CCDC40-related disorder (1)

not provided (1)

Primary ciliary dyskinesia 15 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.70

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.59

M_CAP

Benign

0.032

MetaRNN

Benign

0.011

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.80

PhyloP100

1.8

PrimateAI

Benign

0.30

PROVEAN

Benign

-2.0

REVEL

Benign

0.087

Sift

Benign

0.12

Sift4G

Benign

0.13

Polyphen

0.088

Vest4

0.16

MVP

0.27

MPC

0.17

ClinPred

0.024

GERP RS

3.3

Varity_R

0.048

gMVP

0.14

Mutation Taster

=90/10

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over