rs146360951

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_017950.4(CCDC40):c.2892G>A(p.Ala964Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0003 in 1,614,106 control chromosomes in the GnomAD database, including 3 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 0.00036 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00029 ( 3 hom. )

Consequence

CCDC40
NM_017950.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: -2.39

Publications

1 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 17-80095322-G-A is Benign according to our data. Variant chr17-80095322-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 260964.

BP7

Synonymous conserved (PhyloP=-2.39 with no splicing effect.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000294 (430/1461716) while in subpopulation MID AF = 0.00555 (32/5768). AF 95% confidence interval is 0.00404. There are 3 homozygotes in GnomAdExome4. There are 222 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC40	NM_017950.4	MANE Select	c.2892G>A	p.Ala964Ala	synonymous	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.2892G>A	p.Ala964Ala	synonymous	Exon 18 of 20	ENSP00000380679.4	Q4G0X9-1
CCDC40	ENST00000574799.5	TSL:1	n.2429G>A		non_coding_transcript_exon	Exon 14 of 16
CCDC40	ENST00000897784.1		c.3084G>A	p.Ala1028Ala	synonymous	Exon 19 of 21	ENSP00000567843.1

Frequencies

GnomAD3 genomes

AF:

0.000368

AC:

AN:

152272

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000964

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000385

AC:

AN:

249106

AF XY:

0.000399

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.000319

Gnomad ASJ exome

AF:

0.00288

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.000416

Gnomad OTH exome

AF:

0.00116

GnomAD4 exome

AF:

0.000294

AC:

430

AN:

1461716

Hom.:

Cov.:

AF XY:

0.000305

AC XY:

222

AN XY:

727164

show subpopulations

African (AFR)

AF:

0.000568

AC:

AN:

33480

American (AMR)

AF:

0.000470

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00409

AC:

107

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53250

Middle Eastern (MID)

AF:

0.00555

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000178

AC:

198

AN:

1112004

Other (OTH)

AF:

0.000844

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

102

128

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000361

AC:

AN:

152390

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74520

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41598

American (AMR)

AF:

0.00104

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00403

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000279

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

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:

0.000893

Hom.:

Bravo

AF:

0.000359

EpiCase

AF:

0.000436

EpiControl

AF:

0.000474

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Primary ciliary dyskinesia (2)

not provided (1)

not specified (1)

Primary ciliary dyskinesia 15 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.48

(source)

DANN

Benign

0.46

PhyloP100

-2.4

Mutation Taster

=100/0

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