Variant 17-80040073-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_017950.4(CCDC40):c.355C>A(p.Pro119Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CCDC40
NM_017950.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.262

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1008949).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CCDC40	NM_017950.4 linkuse as main transcript	c.355C>A	p.Pro119Thr	missense_variant	3/20	ENST00000397545.9
CCDC40	NM_001243342.2 linkuse as main transcript	c.355C>A	p.Pro119Thr	missense_variant	3/18
CCDC40	NM_001330508.2 linkuse as main transcript	c.355C>A	p.Pro119Thr	missense_variant	3/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC40	ENST00000397545.9 linkuse as main transcript	c.355C>A	p.Pro119Thr	missense_variant	3/20	5	NM_017950.4	P2	Q4G0X9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248678

Hom.:

AF XY:

0.00000741

AC XY:

AN XY:

135000

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461798

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 01, 2021

This sequence change replaces proline with threonine at codon 119 of the CCDC40 protein (p.Pro119Thr). The proline residue is weakly conserved and there is a small physicochemical difference between proline and threonine. This variant is present in population databases (rs750628862, ExAC 0.009%). This variant has not been reported in the literature in individuals affected with CCDC40-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.44

CADD

Benign

1.4

DANN

Benign

0.47

DEOGEN2

Benign

0.061

.;T;.;.;.;.

Eigen

Benign

-0.82

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.043

LIST_S2

Benign

0.55

T;T;T;T;T;T

M_CAP

Benign

0.0053

MetaRNN

Benign

0.10

T;T;T;T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.69

N;N;N;N;.;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.80

N;N;N;N;.;.

REVEL

Benign

0.079

Sift

Benign

0.065

T;T;D;D;.;.

Sift4G

Benign

0.42

T;T;T;T;D;T

Polyphen

0.34, 1.0

.;B;.;D;.;.

Vest4

0.17

MutPred

0.30

Gain of phosphorylation at P119 (P = 0.0175);Gain of phosphorylation at P119 (P = 0.0175);Gain of phosphorylation at P119 (P = 0.0175);Gain of phosphorylation at P119 (P = 0.0175);.;.;

MVP

0.32

MPC

0.22

ClinPred

0.073

GERP RS

0.14

Varity_R

0.065

gMVP

0.23

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over