rs4889815

Positions:

chr17-80088073-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_017950.4(CCDC40):c.2682G>A(p.Ala894=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 1,613,594 control chromosomes in the GnomAD database, including 198 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 15 hom., cov: 32)

Exomes 𝑓: 0.011 ( 183 hom. )

Consequence

CCDC40
NM_017950.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.923

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 17-80088073-G-A is Benign according to our data. Variant chr17-80088073-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 260962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80088073-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.923 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.01 (1521/151990) while in subpopulation EAS AF= 0.0364 (188/5170). AF 95% confidence interval is 0.0321. There are 15 homozygotes in gnomad4. There are 786 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC40	NM_017950.4 linkuse as main transcript	c.2682G>A	p.Ala894=	synonymous_variant	16/20	ENST00000397545.9	NP_060420.2
CCDC40	NM_001243342.2 linkuse as main transcript	c.2682G>A	p.Ala894=	synonymous_variant	16/18		NP_001230271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC40	ENST00000397545.9 linkuse as main transcript	c.2682G>A	p.Ala894=	synonymous_variant	16/20	5	NM_017950.4	ENSP00000380679	P2	Q4G0X9-1

Frequencies

GnomAD3 genomes

AF:

0.0100

AC:

1522

AN:

151872

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00610

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0115

Gnomad ASJ

AF:

0.00548

Gnomad EAS

AF:

0.0371

Gnomad SAS

AF:

0.00915

Gnomad FIN

AF:

0.0216

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00883

Gnomad OTH

AF:

0.00575

GnomAD3 exomes

AF:

0.0146

AC:

3643

AN:

249398

Hom.:

AF XY:

0.0132

AC XY:

1792

AN XY:

135346

show subpopulations

Gnomad AFR exome

AF:

0.00569

Gnomad AMR exome

AF:

0.0311

Gnomad ASJ exome

AF:

0.00477

Gnomad EAS exome

AF:

0.0352

Gnomad SAS exome

AF:

0.00418

Gnomad FIN exome

AF:

0.0217

Gnomad NFE exome

AF:

0.00997

Gnomad OTH exome

AF:

0.0127

GnomAD4 exome

AF:

0.0112

AC:

16403

AN:

1461604

Hom.:

183

Cov.:

AF XY:

0.0109

AC XY:

7890

AN XY:

727124

show subpopulations

Gnomad4 AFR exome

AF:

0.00436

Gnomad4 AMR exome

AF:

0.0275

Gnomad4 ASJ exome

AF:

0.00524

Gnomad4 EAS exome

AF:

0.0510

Gnomad4 SAS exome

AF:

0.00444

Gnomad4 FIN exome

AF:

0.0207

Gnomad4 NFE exome

AF:

0.00964

Gnomad4 OTH exome

AF:

0.0107

GnomAD4 genome

AF:

0.0100

AC:

1521

AN:

151990

Hom.:

Cov.:

AF XY:

0.0106

AC XY:

786

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.00611

Gnomad4 AMR

AF:

0.0116

Gnomad4 ASJ

AF:

0.00548

Gnomad4 EAS

AF:

0.0364

Gnomad4 SAS

AF:

0.00916

Gnomad4 FIN

AF:

0.0216

Gnomad4 NFE

AF:

0.00883

Gnomad4 OTH

AF:

0.00569

Alfa

AF:

0.00840

Hom.:

Bravo

AF:

0.00991

Asia WGS

AF:

0.0360

AC:

124

AN:

3478

EpiCase

AF:

0.00643

EpiControl

AF:

0.00771

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 05, 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

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 07, 2020	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Primary ciliary dyskinesia 15

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

5.8

DANN

Benign

0.42

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