rs61686936

Positions:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_017950.4(CCDC40):c.2900G>A(p.Arg967His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00256 in 1,614,078 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0027 ( 8 hom. )

Consequence

CCDC40
NM_017950.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014196813).

BP6

Variant 17-80095330-G-A is Benign according to our data. Variant chr17-80095330-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 260965.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=2, Uncertain_significance=2}. Variant chr17-80095330-G-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC40	NM_017950.4 linkuse as main transcript	c.2900G>A	p.Arg967His	missense_variant	18/20	ENST00000397545.9	NP_060420.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC40	ENST00000397545.9 linkuse as main transcript	c.2900G>A	p.Arg967His	missense_variant	18/20	5	NM_017950.4	ENSP00000380679	P2	Q4G0X9-1
CCDC40	ENST00000574799.5 linkuse as main transcript	n.2437G>A		non_coding_transcript_exon_variant	14/16	1
CCDC40	ENST00000572253.5 linkuse as main transcript	n.3151G>A		non_coding_transcript_exon_variant	5/6	2
CCDC40	ENST00000575431.1 linkuse as main transcript	n.544G>A		non_coding_transcript_exon_variant	4/4	3

Frequencies

GnomAD3 genomes

AF:

0.00154

AC:

234

AN:

152258

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00266

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00211

AC:

526

AN:

249080

Hom.:

AF XY:

0.00225

AC XY:

304

AN XY:

135310

show subpopulations

Gnomad AFR exome

AF:

0.000388

Gnomad AMR exome

AF:

0.000869

Gnomad ASJ exome

AF:

0.000796

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00314

Gnomad FIN exome

AF:

0.000974

Gnomad NFE exome

AF:

0.00318

Gnomad OTH exome

AF:

0.000992

GnomAD4 exome

AF:

0.00267

AC:

3900

AN:

1461702

Hom.:

Cov.:

AF XY:

0.00265

AC XY:

1929

AN XY:

727158

show subpopulations

Gnomad4 AFR exome

AF:

0.000508

Gnomad4 AMR exome

AF:

0.000760

Gnomad4 ASJ exome

AF:

0.000650

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.00330

Gnomad4 FIN exome

AF:

0.00101

Gnomad4 NFE exome

AF:

0.00301

Gnomad4 OTH exome

AF:

0.00199

GnomAD4 genome

AF:

0.00154

AC:

234

AN:

152376

Hom.:

Cov.:

AF XY:

0.00154

AC XY:

115

AN XY:

74524

show subpopulations

Gnomad4 AFR

AF:

0.000529

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00269

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.00266

Gnomad4 OTH

AF:

0.00236

Alfa

AF:

0.00342

Hom.:

Bravo

AF:

0.00140

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00208

AC:

ExAC

AF:

0.00215

AC:

261

EpiCase

AF:

0.00273

EpiControl

AF:

0.00338

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	CCDC40: BP4, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 20, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Primary ciliary dyskinesia

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 10, 2019	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

Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

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

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.41

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.73

M_CAP

Benign

0.074

MetaRNN

Benign

0.014

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

MutationTaster

Benign

0.92

PrimateAI

Benign

0.21

PROVEAN

Uncertain

-3.3

REVEL

Benign

0.031

Sift

Benign

0.073

Sift4G

Benign

0.29

Polyphen

0.57

Vest4

0.20

MVP

0.36

MPC

0.30

ClinPred

0.023

GERP RS

-0.58

Varity_R

0.064

gMVP

0.26

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