Genetic Variant NM_017950.4:c.28C>T (chr17-80036690-C-T) – ACMG Classification: Uncertain_significance (0 pts)

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: 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:

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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).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC40	NM_017950.4 link	c.28C>T	p.Arg10Trp	missense_variant, splice_region_variant	Exon 1 of 20	ENST00000397545.9	NP_060420.2	Q4G0X9-1
CCDC40	NM_001243342.2 link	c.28C>T	p.Arg10Trp	missense_variant, splice_region_variant	Exon 1 of 18		NP_001230271.1	Q4G0X9-2
CCDC40	NM_001330508.2 link	c.28C>T	p.Arg10Trp	missense_variant, splice_region_variant	Exon 1 of 11		NP_001317437.1	Q4G0X9-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC40	ENST00000397545.9 link	c.28C>T	p.Arg10Trp	missense_variant, splice_region_variant	Exon 1 of 20	5	NM_017950.4	ENSP00000380679.4		Q4G0X9-1

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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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

.;T;.;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.70

T;T;T;T

M_CAP

Benign

0.021

MetaRNN

Benign

0.10

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

N;N;N;N

PhyloP100

0.59

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.1

N;N;N;N

REVEL

Benign

0.082

Sift

Benign

0.044

D;D;T;T

Sift4G

Uncertain

0.025

D;D;D;D

Polyphen

0.86, 0.94

.;P;.;P

Vest4

0.26

MutPred

0.39

Loss of methylation at R10 (P = 0.02);Loss of methylation at R10 (P = 0.02);Loss of methylation at R10 (P = 0.02);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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NM_017950.4:c.28C>T

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