17-80081958-C-T

Position:

chr17-80081958-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_017950.4(CCDC40):c.1889C>T(p.Ala630Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 1,613,548 control chromosomes in the GnomAD database, including 10,044 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A630A) has been classified as Benign.

Frequency

Genomes: 𝑓 0.085 ( 641 hom., cov: 32)

Exomes 𝑓: 0.11 ( 9403 hom. )

Consequence

CCDC40
NM_017950.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.582

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018564463).

BP6

Variant 17-80081958-C-T is Benign according to our data. Variant chr17-80081958-C-T is described in ClinVar as [Benign]. Clinvar id is 162849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80081958-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.115 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.1889C>T	p.Ala630Val	missense_variant	12/20	ENST00000397545.9	NP_060420.2
CCDC40	NM_001243342.2 linkuse as main transcript	c.1889C>T	p.Ala630Val	missense_variant	12/18		NP_001230271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC40	ENST00000397545.9 linkuse as main transcript	c.1889C>T	p.Ala630Val	missense_variant	12/20	5	NM_017950.4	ENSP00000380679	P2	Q4G0X9-1
CCDC40	ENST00000574799.5 linkuse as main transcript	n.1426C>T		non_coding_transcript_exon_variant	8/16	1
CCDC40	ENST00000374877.7 linkuse as main transcript	c.1889C>T	p.Ala630Val	missense_variant	12/18	5		ENSP00000364011	A2	Q4G0X9-2
CCDC40	ENST00000572253.5 linkuse as main transcript	n.516C>T		non_coding_transcript_exon_variant	1/6	2

Frequencies

GnomAD3 genomes

AF:

0.0854

AC:

12977

AN:

151938

Hom.:

642

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0448

Gnomad AMI

AF:

0.103

Gnomad AMR

AF:

0.0585

Gnomad ASJ

AF:

0.0974

Gnomad EAS

AF:

0.000588

Gnomad SAS

AF:

0.0553

Gnomad FIN

AF:

0.130

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.117

Gnomad OTH

AF:

0.0823

GnomAD3 exomes

AF:

0.0901

AC:

22430

AN:

248870

Hom.:

1261

AF XY:

0.0934

AC XY:

12612

AN XY:

135078

show subpopulations

Gnomad AFR exome

AF:

0.0440

Gnomad AMR exome

AF:

0.0470

Gnomad ASJ exome

AF:

0.0973

Gnomad EAS exome

AF:

0.000167

Gnomad SAS exome

AF:

0.0606

Gnomad FIN exome

AF:

0.138

Gnomad NFE exome

AF:

0.121

Gnomad OTH exome

AF:

0.101

GnomAD4 exome

AF:

0.109

AC:

158777

AN:

1461492

Hom.:

9403

Cov.:

AF XY:

0.108

AC XY:

78411

AN XY:

727040

show subpopulations

Gnomad4 AFR exome

AF:

0.0430

Gnomad4 AMR exome

AF:

0.0487

Gnomad4 ASJ exome

AF:

0.0977

Gnomad4 EAS exome

AF:

0.000327

Gnomad4 SAS exome

AF:

0.0618

Gnomad4 FIN exome

AF:

0.141

Gnomad4 NFE exome

AF:

0.120

Gnomad4 OTH exome

AF:

0.0975

GnomAD4 genome

AF:

0.0853

AC:

12976

AN:

152056

Hom.:

641

Cov.:

AF XY:

0.0844

AC XY:

6270

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.0447

Gnomad4 AMR

AF:

0.0584

Gnomad4 ASJ

AF:

0.0974

Gnomad4 EAS

AF:

0.000589

Gnomad4 SAS

AF:

0.0546

Gnomad4 FIN

AF:

0.130

Gnomad4 NFE

AF:

0.117

Gnomad4 OTH

AF:

0.0819

Alfa

AF:

0.109

Hom.:

1338

Bravo

AF:

0.0793

ExAC

AF:

0.0909

AC:

11014

Asia WGS

AF:

0.0270

AC:

AN:

3478

EpiCase

AF:

0.113

EpiControl

AF:

0.119

ClinVar

Significance: Benign

Submissions summary: Benign:6

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	Ala630Val in exon 12 of CCDC40: This variant is not expected to have clinical si gnificance because it has been identified in 11.3% (21/186) of Finnish chromosom es from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.nih. gov/projects/SNP; dbSNP rs61749058). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 07, 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

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

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.52

CADD

Benign

0.29

DANN

Uncertain

0.98

DEOGEN2

Benign

0.11

.;T

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.058

LIST_S2

Benign

0.62

T;T

MetaRNN

Benign

0.0019

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

M;M

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.23

PROVEAN

Benign

-1.7

N;N

REVEL

Benign

0.028

Sift

Benign

0.22

T;T

Sift4G

Benign

0.44

T;T

Polyphen

0.75

.;P

Vest4

0.12

MPC

0.18

ClinPred

0.010

GERP RS

0.23

Varity_R

0.041

gMVP

0.10

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