rs201293301

Variant summary

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

The NM_017950.4(CCDC40):c.2996G>A(p.Arg999His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000125 in 1,614,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R999C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000098 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

CCDC40
NM_017950.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 0.612

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:

Genome browser will be placed here

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=0.23233888).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC40	NM_017950.4 linkuse as main transcript	c.2996G>A	p.Arg999His	missense_variant	18/20	ENST00000397545.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC40	ENST00000397545.9 linkuse as main transcript	c.2996G>A	p.Arg999His	missense_variant	18/20	5	NM_017950.4	P2	Q4G0X9-1
CCDC40	ENST00000574799.5 linkuse as main transcript	n.2533G>A		non_coding_transcript_exon_variant	14/16	1
CCDC40	ENST00000572253.5 linkuse as main transcript	n.3247G>A		non_coding_transcript_exon_variant	5/6	2

Frequencies

GnomAD3 genomes

AF:

0.0000985

AC:

AN:

152266

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000684

AC:

AN:

248554

Hom.:

AF XY:

0.0000740

AC XY:

AN XY:

135060

show subpopulations

Gnomad AFR exome

AF:

0.0000647

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000557

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000107

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000128

AC:

187

AN:

1461796

Hom.:

Cov.:

AF XY:

0.000127

AC XY:

AN XY:

727188

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000159

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000984

AC:

AN:

152384

Hom.:

Cov.:

AF XY:

0.0000805

AC XY:

AN XY:

74526

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000693

Hom.:

Bravo

AF:

0.0000831

ExAC

AF:

0.0000908

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	Jan 14, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 27, 2024	The c.2996G>A (p.R999H) alteration is located in exon 18 (coding exon 18) of the CCDC40 gene. This alteration results from a G to A substitution at nucleotide position 2996, causing the arginine (R) at amino acid position 999 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 19, 2022	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 999 of the CCDC40 protein (p.Arg999His). This variant is present in population databases (rs201293301, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CCDC40-related conditions. ClinVar contains an entry for this variant (Variation ID: 454887). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -

Primary ciliary dyskinesia 15

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 03, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.42

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.43

Eigen

Benign

-0.054

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.83

M_CAP

Benign

0.061

MetaRNN

Benign

0.23

MetaSVM

Benign

-0.82

MutationAssessor

Uncertain

2.7

MutationTaster

Benign

1.0

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-3.4

REVEL

Benign

0.094

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.037

Polyphen

1.0

Vest4

0.32

MVP

0.52

MPC

0.77

ClinPred

0.42

GERP RS

1.1

Varity_R

0.095

gMVP

0.16

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