17-80036690-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_017950.4(CCDC40):c.28C>T(p.Arg10Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000382 in 1,310,546 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 19/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R10G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000038 ( 0 hom. )

Consequence

CCDC40
NM_017950.4 missense, splice_region

Scores

Splicing: ADA: 0.0002951

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.592

Publications

0 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: ClinGen, PanelApp Australia, Ambry Genetics, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
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.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10458195).

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.28C>T	p.Arg10Trp	missense splice_region	Exon 1 of 20	NP_060420.2
CCDC40	NM_001243342.2		c.28C>T	p.Arg10Trp	missense splice_region	Exon 1 of 18	NP_001230271.1	Q4G0X9-2
CCDC40	NM_001330508.2		c.28C>T	p.Arg10Trp	missense splice_region	Exon 1 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.28C>T	p.Arg10Trp	missense splice_region	Exon 1 of 20	ENSP00000380679.4	Q4G0X9-1
CCDC40	ENST00000374876.4	TSL:1	c.28C>T	p.Arg10Trp	missense splice_region	Exon 1 of 9	ENSP00000364010.4	Q4G0X9-5
CCDC40	ENST00000574099.1	TSL:4	c.-129C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	ENSP00000460002.1	I3L2X6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000382

AC:

AN:

1310546

Hom.:

Cov.:

AF XY:

0.00000466

AC XY:

AN XY:

644322

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27724

American (AMR)

AF:

0.00

AC:

AN:

27080

Ashkenazi Jewish (ASJ)

AF:

0.0000437

AC:

AN:

22900

East Asian (EAS)

AF:

0.00

AC:

AN:

30162

South Asian (SAS)

AF:

0.0000142

AC:

AN:

70530

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31758

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5234

European-Non Finnish (NFE)

AF:

9.61e-7

AC:

AN:

1041020

Other (OTH)

AF:

0.0000369

AC:

AN:

54138

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.415

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.034

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.70

M_CAP

Benign

0.021

MetaRNN

Benign

0.10

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

PhyloP100

0.59

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.1

REVEL

Benign

0.082

Sift

Benign

0.044

Sift4G

Uncertain

0.025

Polyphen

0.86

Vest4

0.26

MutPred

0.39

Loss of methylation at R10 (P = 0.02)

MVP

0.10

MPC

0.25

ClinPred

0.21

GERP RS

-1.7

PromoterAI

0.033

Neutral

(source)

Varity_R

0.069

gMVP

0.082

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00030

dbscSNV1_RF

Benign

0.15

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over