NM_017950.4:c.850G>C

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_017950.4(CCDC40):c.850G>C(p.Asp284His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0024 in 1,608,890 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0016 ( 3 hom., cov: 31)

Exomes 𝑓: 0.0025 ( 21 hom. )

Consequence

CCDC40
NM_017950.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:6

Conservation

PhyloP100: 0.526

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:

ENSG00000289689 (HGNC:):

ENSG00000289689 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01399526).

BP6

Variant 17-80048756-G-C is Benign according to our data. Variant chr17-80048756-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 260979.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=3, Uncertain_significance=1}. Variant chr17-80048756-G-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0016 (244/152326) while in subpopulation SAS AF= 0.00871 (42/4824). AF 95% confidence interval is 0.00662. There are 3 homozygotes in gnomad4. There are 132 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC40	NM_017950.4 link	c.850G>C	p.Asp284His	missense_variant	Exon 5 of 20	ENST00000397545.9	NP_060420.2	Q4G0X9-1
CCDC40	NM_001243342.2 link	c.850G>C	p.Asp284His	missense_variant	Exon 5 of 18		NP_001230271.1	Q4G0X9-2
CCDC40	NM_001330508.2 link	c.850G>C	p.Asp284His	missense_variant	Exon 5 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.850G>C	p.Asp284His	missense_variant	Exon 5 of 20	5	NM_017950.4	ENSP00000380679.4		Q4G0X9-1

Frequencies

GnomAD3 genomes

AF:

0.00160

AC:

243

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.000786

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00829

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00209

Gnomad OTH

AF:

0.00431

GnomAD3 exomes

AF:

0.00283

AC:

666

AN:

235048

Hom.:

AF XY:

0.00336

AC XY:

430

AN XY:

127810

show subpopulations

Gnomad AFR exome

AF:

0.000344

Gnomad AMR exome

AF:

0.00103

Gnomad ASJ exome

AF:

0.00541

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00941

Gnomad FIN exome

AF:

0.0000994

Gnomad NFE exome

AF:

0.00259

Gnomad OTH exome

AF:

0.00379

GnomAD4 exome

AF:

0.00248

AC:

3616

AN:

1456564

Hom.:

Cov.:

AF XY:

0.00271

AC XY:

1965

AN XY:

724066

show subpopulations

Gnomad4 AFR exome

AF:

0.00108

Gnomad4 AMR exome

AF:

0.00132

Gnomad4 ASJ exome

AF:

0.00622

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00875

Gnomad4 FIN exome

AF:

0.000227

Gnomad4 NFE exome

AF:

0.00207

Gnomad4 OTH exome

AF:

0.00322

GnomAD4 genome

AF:

0.00160

AC:

244

AN:

152326

Hom.:

Cov.:

AF XY:

0.00177

AC XY:

132

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.000409

Gnomad4 AMR

AF:

0.000785

Gnomad4 ASJ

AF:

0.00375

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00871

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00209

Gnomad4 OTH

AF:

0.00427

Alfa

AF:

0.00242

Hom.:

Bravo

AF:

0.00149

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000721

AC:

ESP6500EA

AF:

0.00322

AC:

ExAC

AF:

0.00281

AC:

340

Asia WGS

AF:

0.00346

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:2

Mar 20, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Asp284His in exon 5 of CCDC40: This variant is not expected to have clinical s ignificance because it has been identified in 1% (129/1262) of South Asian chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs201042940). -

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary ciliary dyskinesia

Benign:2

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 15, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided

Benign:2

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CCDC40: BP4, BS2 -

Mar 11, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 33574797) -

Male infertility

Uncertain:1

MAGI's Lab - Research, MAGI Group

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: provider interpretation

- -

Primary ciliary dyskinesia 15

Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.13

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.57

.;D;.;.

Eigen

Uncertain

0.26

Eigen_PC

Benign

0.12

FATHMM_MKL

Benign

0.51

LIST_S2

Uncertain

0.88

D;D;D;D

MetaRNN

Benign

0.014

T;T;T;T

MetaSVM

Uncertain

-0.26

MutationAssessor

Uncertain

2.8

M;M;M;M

PrimateAI

Benign

0.41

PROVEAN

Pathogenic

-4.7

D;D;D;D

REVEL

Benign

0.17

Sift

Uncertain

0.0040

D;D;D;D

Sift4G

Uncertain

0.0080

D;D;D;D

Polyphen

1.0

.;D;.;D

Vest4

0.53

MVP

0.68

MPC

0.76

ClinPred

0.049

GERP RS

1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.23

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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