Genetic Variant CCDC40:p.Ala7Ser (chr17-80036681-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_017950.4(CCDC40):c.19G>T(p.Ala7Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000764 in 1,308,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 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. A7T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.6e-7 ( 0 hom. )

Consequence

CCDC40
NM_017950.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.93

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.048728615).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC40	NM_017950.4 link	c.19G>T	p.Ala7Ser	missense_variant	Exon 1 of 20	ENST00000397545.9	NP_060420.2	Q4G0X9-1
CCDC40	NM_001243342.2 link	c.19G>T	p.Ala7Ser	missense_variant	Exon 1 of 18		NP_001230271.1	Q4G0X9-2
CCDC40	NM_001330508.2 link	c.19G>T	p.Ala7Ser	missense_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.19G>T	p.Ala7Ser	missense_variant	Exon 1 of 20	5	NM_017950.4	ENSP00000380679.4		Q4G0X9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.64e-7

AC:

AN:

1308554

Hom.:

Cov.:

AF XY:

0.00000155

AC XY:

AN XY:

643192

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

27582

American (AMR)

AF:

0.00

AC:

AN:

26804

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22764

East Asian (EAS)

AF:

0.00

AC:

AN:

29944

South Asian (SAS)

AF:

0.00

AC:

AN:

70094

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31764

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5154

European-Non Finnish (NFE)

AF:

9.61e-7

AC:

AN:

1040392

Other (OTH)

AF:

0.00

AC:

AN:

54056

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

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

0.14

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.11

(source)

DANN

Benign

0.54

DEOGEN2

Benign

0.021

.;T;.;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0060

LIST_S2

Benign

0.48

T;T;T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.049

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.55

N;N;N;N

PhyloP100

-2.9

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.080

N;N;N;N

REVEL

Benign

0.010

Sift

Benign

0.46

T;T;T;T

Sift4G

Benign

0.77

T;T;T;T

Polyphen

0.10, 0.53

.;B;.;P

Vest4

0.083

MutPred

0.35

Gain of phosphorylation at A7 (P = 0.0043);Gain of phosphorylation at A7 (P = 0.0043);Gain of phosphorylation at A7 (P = 0.0043);Gain of phosphorylation at A7 (P = 0.0043);

MVP

0.048

MPC

0.16

ClinPred

0.12

GERP RS

-3.3

PromoterAI

-0.0013

Neutral

(source)

Varity_R

0.027

gMVP

0.027

Mutation Taster

=99/1

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over