17-80095330-G-T

Position:

chr17-80095330-G-T

Variant summary

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

The NM_017950.4(CCDC40):c.2900G>T(p.Arg967Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00489 in 1,614,062 control chromosomes in the GnomAD database, including 355 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R967H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.026 ( 184 hom., cov: 34)

Exomes 𝑓: 0.0027 ( 171 hom. )

Consequence

CCDC40
NM_017950.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.983

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:

CCDC40 (HGNC:):

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=0.0056913495).

BP6

Variant 17-80095330-G-T is Benign according to our data. Variant chr17-80095330-G-T is described in ClinVar as [Benign]. Clinvar id is 226493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.087 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC40	NM_017950.4 linkuse as main transcript	c.2900G>T	p.Arg967Leu	missense_variant	18/20	ENST00000397545.9	NP_060420.2	Q4G0X9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CCDC40	ENST00000397545.9 linkuse as main transcript	c.2900G>T	p.Arg967Leu	missense_variant	18/20	5	NM_017950.4	ENSP00000380679.4	Q4G0X9-1
CCDC40	ENST00000574799.5 linkuse as main transcript	n.2437G>T		non_coding_transcript_exon_variant	14/16	1
CCDC40	ENST00000572253.5 linkuse as main transcript	n.3151G>T		non_coding_transcript_exon_variant	5/6	2
CCDC40	ENST00000575431.1 linkuse as main transcript	n.544G>T		non_coding_transcript_exon_variant	4/4	3

Frequencies

GnomAD3 genomes

AF:

0.0253

AC:

3859

AN:

152238

Hom.:

178

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0890

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00759

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.0172

GnomAD3 exomes

AF:

0.00655

AC:

1632

AN:

249080

Hom.:

AF XY:

0.00488

AC XY:

660

AN XY:

135310

show subpopulations

Gnomad AFR exome

AF:

0.0924

Gnomad AMR exome

AF:

0.00446

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000359

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000230

Gnomad OTH exome

AF:

0.00198

GnomAD4 exome

AF:

0.00274

AC:

4000

AN:

1461708

Hom.:

171

Cov.:

AF XY:

0.00244

AC XY:

1774

AN XY:

727160

show subpopulations

Gnomad4 AFR exome

AF:

0.0947

Gnomad4 AMR exome

AF:

0.00510

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000301

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.000165

Gnomad4 OTH exome

AF:

0.00599

GnomAD4 genome

AF:

0.0255

AC:

3887

AN:

152354

Hom.:

184

Cov.:

AF XY:

0.0246

AC XY:

1831

AN XY:

74512

show subpopulations

Gnomad4 AFR

AF:

0.0894

Gnomad4 AMR

AF:

0.00758

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.0170

Alfa

AF:

0.000199

Hom.:

Bravo

AF:

0.0295

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.0849

AC:

367

ESP6500EA

AF:

0.000235

AC:

ExAC

AF:

0.00784

AC:

951

EpiCase

AF:

0.000382

EpiControl

AF:

0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:7

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	Aug 12, 2015	p.Arg967Leu in exon 18 of CCDC40: This variant is not expected to have clinical significance it has been identified in 8.8% (861/9720) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP r s61686936). -

Primary ciliary dyskinesia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 02, 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. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	This variant is associated with the following publications: (PMID: 31213628) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Primary ciliary dyskinesia 15

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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

0.24

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.58

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.72

MetaRNN

Benign

0.0057

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

PrimateAI

Benign

0.21

PROVEAN

Pathogenic

-5.2

REVEL

Benign

0.068

Sift

Benign

0.036

Sift4G

Benign

0.094

Polyphen

0.72

Vest4

0.41

MVP

0.53

MPC

0.41

ClinPred

0.028

GERP RS

-0.58

Varity_R

0.17

gMVP

0.45

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