17-80049923-C-T

Position:

chr17-80049923-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_017950.4(CCDC40):c.873C>T(p.Phe291Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0916 in 1,613,484 control chromosomes in the GnomAD database, including 7,538 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 835 hom., cov: 31)

Exomes 𝑓: 0.091 ( 6703 hom. )

Consequence

CCDC40
NM_017950.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.21

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.33).

BP6

Variant 17-80049923-C-T is Benign according to our data. Variant chr17-80049923-C-T is described in ClinVar as [Benign]. Clinvar id is 178708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80049923-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=1.21 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.153 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.873C>T	p.Phe291Phe	synonymous_variant	6/20	ENST00000397545.9	NP_060420.2	Q4G0X9-1
CCDC40	NM_001243342.2 linkuse as main transcript	c.873C>T	p.Phe291Phe	synonymous_variant	6/18		NP_001230271.1	Q4G0X9-2
CCDC40	NM_001330508.2 linkuse as main transcript	c.873C>T	p.Phe291Phe	synonymous_variant	6/11		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.873C>T	p.Phe291Phe	synonymous_variant	6/20	5	NM_017950.4	ENSP00000380679.4		Q4G0X9-1

Frequencies

GnomAD3 genomes

AF:

0.100

AC:

15268

AN:

151974

Hom.:

837

Cov.:

show subpopulations

Gnomad AFR

AF:

0.114

Gnomad AMI

AF:

0.0176

Gnomad AMR

AF:

0.0651

Gnomad ASJ

AF:

0.133

Gnomad EAS

AF:

0.162

Gnomad SAS

AF:

0.112

Gnomad FIN

AF:

0.110

Gnomad MID

AF:

0.178

Gnomad NFE

AF:

0.0918

Gnomad OTH

AF:

0.114

GnomAD3 exomes

AF:

0.0991

AC:

24721

AN:

249498

Hom.:

1398

AF XY:

0.102

AC XY:

13800

AN XY:

135378

show subpopulations

Gnomad AFR exome

AF:

0.114

Gnomad AMR exome

AF:

0.0525

Gnomad ASJ exome

AF:

0.132

Gnomad EAS exome

AF:

0.162

Gnomad SAS exome

AF:

0.126

Gnomad FIN exome

AF:

0.110

Gnomad NFE exome

AF:

0.0883

Gnomad OTH exome

AF:

0.110

GnomAD4 exome

AF:

0.0907

AC:

132589

AN:

1461390

Hom.:

6703

Cov.:

AF XY:

0.0924

AC XY:

67204

AN XY:

727016

show subpopulations

Gnomad4 AFR exome

AF:

0.115

Gnomad4 AMR exome

AF:

0.0563

Gnomad4 ASJ exome

AF:

0.130

Gnomad4 EAS exome

AF:

0.182

Gnomad4 SAS exome

AF:

0.123

Gnomad4 FIN exome

AF:

0.110

Gnomad4 NFE exome

AF:

0.0830

Gnomad4 OTH exome

AF:

0.0990

GnomAD4 genome

AF:

0.100

AC:

15264

AN:

152094

Hom.:

835

Cov.:

AF XY:

0.102

AC XY:

7574

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.114

Gnomad4 AMR

AF:

0.0650

Gnomad4 ASJ

AF:

0.133

Gnomad4 EAS

AF:

0.162

Gnomad4 SAS

AF:

0.112

Gnomad4 FIN

AF:

0.110

Gnomad4 NFE

AF:

0.0918

Gnomad4 OTH

AF:

0.114

Alfa

AF:

0.0941

Hom.:

668

Bravo

AF:

0.0962

Asia WGS

AF:

0.118

AC:

410

AN:

3478

EpiCase

AF:

0.0938

EpiControl

AF:

0.0921

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	Phe291Phe in exon 6 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 10.5% (417/3954) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2289531). -

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	Jul 08, 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 05, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Primary ciliary dyskinesia 15

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.33

CADD

Benign

8.3

DANN

Benign

0.70

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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