Genetic Variant CCDC40:p.Glu511Lys (chr17-80065575-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_017950.4(CCDC40):c.1531G>A(p.Glu511Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00118 in 1,612,864 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E511Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0064 ( 10 hom., cov: 29)

Exomes 𝑓: 0.00064 ( 14 hom. )

Consequence

CCDC40
NM_017950.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 6.97

Publications

7 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:

ENSG00000289689 (HGNC:):

ENSG00000289689 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010186464).

BP6

Variant 17-80065575-G-A is Benign according to our data. Variant chr17-80065575-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 178709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00642 (977/152208) while in subpopulation AFR AF = 0.0225 (935/41554). AF 95% confidence interval is 0.0213. There are 10 homozygotes in GnomAd4. There are 447 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 10 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CCDC40	NM_017950.4	MANE Select	c.1531G>A	p.Glu511Lys	missense	Exon 10 of 20	NP_060420.2
CCDC40	NM_001243342.2		c.1531G>A	p.Glu511Lys	missense	Exon 10 of 18	NP_001230271.1	Q4G0X9-2
CCDC40	NM_001330508.2		c.1531G>A	p.Glu511Lys	missense	Exon 10 of 11	NP_001317437.1	Q4G0X9-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CCDC40	ENST00000397545.9	TSL:5 MANE Select	c.1531G>A	p.Glu511Lys	missense	Exon 10 of 20	ENSP00000380679.4	Q4G0X9-1
CCDC40	ENST00000374876.4	TSL:1	c.1318-508G>A		intron	N/A	ENSP00000364010.4	Q4G0X9-5
CCDC40	ENST00000574799.5	TSL:1	n.1068G>A		non_coding_transcript_exon	Exon 6 of 16

Frequencies

GnomAD3 genomes

AF:

0.00639

AC:

972

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0224

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00170

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00155

AC:

385

AN:

247998

AF XY:

0.00106

show subpopulations

Gnomad AFR exome

AF:

0.0228

Gnomad AMR exome

AF:

0.000783

Gnomad ASJ exome

AF:

0.000200

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000446

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000637

AC:

930

AN:

1460656

Hom.:

Cov.:

AF XY:

0.000557

AC XY:

405

AN XY:

726650

show subpopulations

African (AFR)

AF:

0.0229

AC:

765

AN:

33472

American (AMR)

AF:

0.000805

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86226

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52494

Middle Eastern (MID)

AF:

0.000351

AC:

AN:

5690

European-Non Finnish (NFE)

AF:

0.0000324

AC:

AN:

1111882

Other (OTH)

AF:

0.00142

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

111

166

222

277

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<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:

0.00642

AC:

977

AN:

152208

Hom.:

Cov.:

AF XY:

0.00601

AC XY:

447

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.0225

AC:

935

AN:

41554

American (AMR)

AF:

0.00170

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5108

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68016

Other (OTH)

AF:

0.00284

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

145

193

241

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00199

Hom.:

Bravo

AF:

0.00740

ESP6500AA

AF:

0.0240

AC:

102

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00196

AC:

237

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Primary ciliary dyskinesia (2)

Primary ciliary dyskinesia 15 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.40

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.91

MetaRNN

Benign

0.010

MetaSVM

Benign

-0.44

MutationAssessor

Pathogenic

3.0

PhyloP100

7.0

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.5

REVEL

Uncertain

0.33

Sift

Pathogenic

0.0

Sift4G

Benign

0.066

Polyphen

1.0

Vest4

0.73

MVP

0.71

MPC

0.76

ClinPred

0.047

GERP RS

5.1

Varity_R

0.52

gMVP

0.35

Mutation Taster

=79/21

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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