rs74000351

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_017950.4(CCDC40):c.504G>A(p.Pro168Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00518 in 1,613,952 control chromosomes in the GnomAD database, including 309 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.026 ( 176 hom., cov: 32)

Exomes 𝑓: 0.0030 ( 133 hom. )

Consequence

CCDC40
NM_017950.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -2.97

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.99).

BP6

Variant 17-80040222-G-A is Benign according to our data. Variant chr17-80040222-G-A is described in ClinVar as [Benign]. Clinvar id is 226494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.97 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0844 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.504G>A	p.Pro168Pro	synonymous_variant	3/20	ENST00000397545.9	NP_060420.2	Q4G0X9-1
CCDC40	NM_001243342.2 linkuse as main transcript	c.504G>A	p.Pro168Pro	synonymous_variant	3/18		NP_001230271.1	Q4G0X9-2
CCDC40	NM_001330508.2 linkuse as main transcript	c.504G>A	p.Pro168Pro	synonymous_variant	3/11		NP_001317437.1	Q4G0X9-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC40	ENST00000397545.9 linkuse as main transcript	c.504G>A	p.Pro168Pro	synonymous_variant	3/20	5	NM_017950.4	ENSP00000380679.4		Q4G0X9-1

Frequencies

GnomAD3 genomes

AF:

0.0256

AC:

3903

AN:

152174

Hom.:

176

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0867

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0119

Gnomad ASJ

AF:

0.00979

Gnomad EAS

AF:

0.00250

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000559

Gnomad OTH

AF:

0.0182

GnomAD3 exomes

AF:

0.00735

AC:

1824

AN:

248174

Hom.:

AF XY:

0.00580

AC XY:

782

AN XY:

134910

show subpopulations

Gnomad AFR exome

AF:

0.0921

Gnomad AMR exome

AF:

0.00455

Gnomad ASJ exome

AF:

0.00858

Gnomad EAS exome

AF:

0.00312

Gnomad SAS exome

AF:

0.000425

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000606

Gnomad OTH exome

AF:

0.00464

GnomAD4 exome

AF:

0.00304

AC:

4440

AN:

1461660

Hom.:

133

Cov.:

AF XY:

0.00274

AC XY:

1990

AN XY:

727134

show subpopulations

Gnomad4 AFR exome

AF:

0.0892

Gnomad4 AMR exome

AF:

0.00544

Gnomad4 ASJ exome

AF:

0.00750

Gnomad4 EAS exome

AF:

0.00169

Gnomad4 SAS exome

AF:

0.000661

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000339

Gnomad4 OTH exome

AF:

0.00697

GnomAD4 genome

AF:

0.0257

AC:

3915

AN:

152292

Hom.:

176

Cov.:

AF XY:

0.0243

AC XY:

1807

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.0868

Gnomad4 AMR

AF:

0.0118

Gnomad4 ASJ

AF:

0.00979

Gnomad4 EAS

AF:

0.00251

Gnomad4 SAS

AF:

0.000828

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000559

Gnomad4 OTH

AF:

0.0180

Alfa

AF:

0.00850

Hom.:

Bravo

AF:

0.0303

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.000981

EpiControl

AF:

0.000830

ClinVar

Significance: Benign

Submissions summary: Benign:8

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	Pro168Pro in exon 3 of CCDC40: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 8.5% (336/3946) of African American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs74000351). -

Primary ciliary dyskinesia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 25, 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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -

Primary ciliary dyskinesia 15

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
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

BayesDel_noAF

Benign

-0.99

CADD

Benign

1.4

DANN

Benign

0.51

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