rs59978698

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_017950.4(CCDC40):c.1531G>A(p.Glu511Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00118 in 1,612,864 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0064 ( 10 hom., cov: 29)

Exomes 𝑓: 0.00064 ( 14 hom. )

Consequence

CCDC40
NM_017950.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 6.97

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:

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=0.010186464).

BP6

Variant 17-80065575-G-A is Benign according to our data. Variant chr17-80065575-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 178709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80065575-G-A is described in Lovd as [Likely_benign]. Variant chr17-80065575-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00642 (977/152208) while in subpopulation AFR AF= 0.0225 (935/41554). AF 95% confidence interval is 0.0213. There are 10 homozygotes in gnomad4. There are 447 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC40	NM_017950.4 linkuse as main transcript	c.1531G>A	p.Glu511Lys	missense_variant	10/20	ENST00000397545.9	NP_060420.2	Q4G0X9-1
CCDC40	NM_001243342.2 linkuse as main transcript	c.1531G>A	p.Glu511Lys	missense_variant	10/18		NP_001230271.1	Q4G0X9-2
CCDC40	NM_001330508.2 linkuse as main transcript	c.1531G>A	p.Glu511Lys	missense_variant	10/11		NP_001317437.1	Q4G0X9-4
LOC124904074	XR_007065931.1 linkuse as main transcript	n.305+5657C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC40	ENST00000397545.9 linkuse as main transcript	c.1531G>A	p.Glu511Lys	missense_variant	10/20	5	NM_017950.4	ENSP00000380679.4		Q4G0X9-1

Frequencies

GnomAD3 genomes

AF:

0.00639

AC:

972

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0224

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00170

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00155

AC:

385

AN:

247998

Hom.:

AF XY:

0.00106

AC XY:

143

AN XY:

135030

show subpopulations

Gnomad AFR exome

AF:

0.0228

Gnomad AMR exome

AF:

0.000783

Gnomad ASJ exome

AF:

0.000200

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000446

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000637

AC:

930

AN:

1460656

Hom.:

Cov.:

AF XY:

0.000557

AC XY:

405

AN XY:

726650

show subpopulations

Gnomad4 AFR exome

AF:

0.0229

Gnomad4 AMR exome

AF:

0.000805

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000324

Gnomad4 OTH exome

AF:

0.00142

GnomAD4 genome

AF:

0.00642

AC:

977

AN:

152208

Hom.:

Cov.:

AF XY:

0.00601

AC XY:

447

AN XY:

74410

show subpopulations

Gnomad4 AFR

AF:

0.0225

Gnomad4 AMR

AF:

0.00170

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.000235

Hom.:

Bravo

AF:

0.00740

ESP6500AA

AF:

0.0240

AC:

102

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00196

AC:

237

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Glu511Lys in exon 10 of CCDC40: This variant is not expected to have clinical si gnificance because it has been identified in 2.4% (102/4244) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs59978698). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Primary ciliary dyskinesia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 15, 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. -

Primary ciliary dyskinesia 15

Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.40

.;T;.

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.91

D;D;D

MetaRNN

Benign

0.010

T;T;T

MetaSVM

Benign

-0.44

MutationAssessor

Pathogenic

3.0

M;M;M

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.5

D;D;D

REVEL

Uncertain

0.33

Sift

Pathogenic

0.0

D;D;T

Sift4G

Benign

0.066

T;T;D

Polyphen

1.0

.;D;.

Vest4

0.73

MVP

0.71

MPC

0.76

ClinPred

0.047

GERP RS

5.1

Varity_R

0.52

gMVP

0.35

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