Genetic Variant NM_017950.4:c.2832+462_2832+463insCACGGGACGCGCGCAGGCACGTGCACGAACAACAC (chr17-80090346-A-ACACGGGACGCGCGCAGGCACGTGCACGAACAACAC) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_017950.4(CCDC40):c.2832+462_2832+463insCACGGGACGCGCGCAGGCACGTGCACGAACAACAC variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000052 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000094 ( 9 hom. )

Failed GnomAD Quality Control

Consequence

CCDC40
NM_017950.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0180

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: 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC40	NM_017950.4 link	c.2832+462_2832+463insCACGGGACGCGCGCAGGCACGTGCACGAACAACAC		intron_variant	Intron 17 of 19	ENST00000397545.9	NP_060420.2	Q4G0X9-1
CCDC40	NM_001243342.2 link	c.3040_3041insCACGGGACGCGCGCAGGCACGTGCACGAACAACAC	p.Arg1014ThrfsTer40	frameshift_variant	Exon 18 of 18		NP_001230271.1	Q4G0X9-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC40	ENST00000397545.9 link	c.2832+462_2832+463insCACGGGACGCGCGCAGGCACGTGCACGAACAACAC		intron_variant	Intron 17 of 19	5	NM_017950.4	ENSP00000380679.4		Q4G0X9-1

Frequencies

GnomAD3 genomes

AF:

0.0000517

AC:

AN:

19356

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000138

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000354

AC:

AN:

65002

AF XY:

0.000339

show subpopulations

Gnomad AFR exome

AF:

0.000843

Gnomad AMR exome

AF:

0.000153

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00199

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000218

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000941

AC:

AN:

414252

Hom.:

Cov.:

AF XY:

0.000109

AC XY:

AN XY:

210730

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000315

AC:

AN:

12706

American (AMR)

AF:

0.00

AC:

AN:

17058

Ashkenazi Jewish (ASJ)

AF:

0.000130

AC:

AN:

7698

East Asian (EAS)

AF:

0.0000634

AC:

AN:

15784

South Asian (SAS)

AF:

0.000172

AC:

AN:

29050

European-Finnish (FIN)

AF:

0.000194

AC:

AN:

15482

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1824

European-Non Finnish (NFE)

AF:

0.0000813

AC:

AN:

295310

Other (OTH)

AF:

0.0000517

AC:

AN:

19340

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000376076), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.373

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.0000517

AC:

AN:

19356

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

9544

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

6254

American (AMR)

AF:

0.00

AC:

AN:

3176

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

270

East Asian (EAS)

AF:

0.00

AC:

AN:

870

South Asian (SAS)

AF:

0.00

AC:

AN:

370

European-Finnish (FIN)

AF:

0.00

AC:

AN:

768

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000138

AC:

AN:

7226

Other (OTH)

AF:

0.00

AC:

AN:

240

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.018

Mutation Taster

=191/9

polymorphism

(source)

Splicing

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over