rs60684213

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_017950.4(CCDC40):c.2323G>A(p.Val775Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0862 in 1,614,060 control chromosomes in the GnomAD database, including 7,071 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V775V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.11 ( 1255 hom., cov: 32)

Exomes 𝑓: 0.083 ( 5816 hom. )

Consequence

CCDC40
NM_017950.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.64

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017687082).

BP6

Variant 17-80086090-G-A is Benign according to our data. Variant chr17-80086090-G-A is described in ClinVar as [Benign]. Clinvar id is 162851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80086090-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.203 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC40	NM_017950.4 linkuse as main transcript	c.2323G>A	p.Val775Met	missense_variant	14/20	ENST00000397545.9
CCDC40	NM_001243342.2 linkuse as main transcript	c.2323G>A	p.Val775Met	missense_variant	14/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC40	ENST00000397545.9 linkuse as main transcript	c.2323G>A	p.Val775Met	missense_variant	14/20	5	NM_017950.4	P2	Q4G0X9-1
CCDC40	ENST00000574799.5 linkuse as main transcript	n.1860G>A		non_coding_transcript_exon_variant	10/16	1
CCDC40	ENST00000374877.7 linkuse as main transcript	c.2323G>A	p.Val775Met	missense_variant	14/18	5		A2	Q4G0X9-2
CCDC40	ENST00000572253.5 linkuse as main transcript	n.950G>A		non_coding_transcript_exon_variant	3/6	2

Frequencies

GnomAD3 genomes

AF:

0.115

AC:

17475

AN:

152128

Hom.:

1251

Cov.:

show subpopulations

Gnomad AFR

AF:

0.207

Gnomad AMI

AF:

0.0713

Gnomad AMR

AF:

0.0645

Gnomad ASJ

AF:

0.104

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.0824

Gnomad FIN

AF:

0.115

Gnomad MID

AF:

0.166

Gnomad NFE

AF:

0.0819

Gnomad OTH

AF:

0.112

GnomAD3 exomes

AF:

0.0880

AC:

21937

AN:

249388

Hom.:

1273

AF XY:

0.0886

AC XY:

11997

AN XY:

135368

show subpopulations

Gnomad AFR exome

AF:

0.211

Gnomad AMR exome

AF:

0.0525

Gnomad ASJ exome

AF:

0.106

Gnomad EAS exome

AF:

0.000612

Gnomad SAS exome

AF:

0.102

Gnomad FIN exome

AF:

0.111

Gnomad NFE exome

AF:

0.0855

Gnomad OTH exome

AF:

0.0949

GnomAD4 exome

AF:

0.0832

AC:

121580

AN:

1461812

Hom.:

5816

Cov.:

AF XY:

0.0839

AC XY:

61034

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.217

Gnomad4 AMR exome

AF:

0.0559

Gnomad4 ASJ exome

AF:

0.105

Gnomad4 EAS exome

AF:

0.000378

Gnomad4 SAS exome

AF:

0.0990

Gnomad4 FIN exome

AF:

0.114

Gnomad4 NFE exome

AF:

0.0795

Gnomad4 OTH exome

AF:

0.0884

GnomAD4 genome

AF:

0.115

AC:

17488

AN:

152248

Hom.:

1255

Cov.:

AF XY:

0.114

AC XY:

8523

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.207

Gnomad4 AMR

AF:

0.0643

Gnomad4 ASJ

AF:

0.104

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.0825

Gnomad4 FIN

AF:

0.115

Gnomad4 NFE

AF:

0.0819

Gnomad4 OTH

AF:

0.111

Alfa

AF:

0.0831

Hom.:

948

Bravo

AF:

0.115

TwinsUK

AF:

0.0771

AC:

286

ALSPAC

AF:

0.0815

AC:

314

ESP6500AA

AF:

0.185

AC:

775

ESP6500EA

AF:

0.0846

AC:

711

ExAC

AF:

0.0915

AC:

11069

Asia WGS

AF:

0.0530

AC:

186

AN:

3478

EpiCase

AF:

0.0858

EpiControl

AF:

0.0860

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Val775Met in exon 14 of CCDC40: This variant is not expected to have clinical si gnificance because it has been identified in 18.5% (775/4194) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs60684213). -

Primary ciliary dyskinesia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 27, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 05, 2018

- -

Primary ciliary dyskinesia 15

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.69

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.049

.;T

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.69

T;T

MetaRNN

Benign

0.0018

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

L;L

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.37

PROVEAN

Benign

0.74

N;N

REVEL

Benign

0.035

Sift

Benign

0.15

T;T

Sift4G

Benign

0.12

T;T

Polyphen

0.19

.;B

Vest4

0.080

MPC

0.21

ClinPred

0.0066

GERP RS

2.7

Varity_R

0.027

gMVP

0.11

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