rs148900528

Positions:

chr17-80099770-T-C

Variant summary

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

The NM_017950.4(CCDC40):c.3424T>C(p.Ser1142Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000668 in 1,612,568 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0033 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00040 ( 3 hom. )

Consequence

CCDC40
NM_017950.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.15

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=0.0039035678).

BP6

Variant 17-80099770-T-C is Benign according to our data. Variant chr17-80099770-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 195521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80099770-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00328 (498/152040) while in subpopulation AFR AF= 0.0115 (477/41480). AF 95% confidence interval is 0.0106. There are 1 homozygotes in gnomad4. There are 211 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC40	NM_017950.4 linkuse as main transcript	c.3424T>C	p.Ser1142Pro	missense_variant	20/20	ENST00000397545.9	NP_060420.2	Q4G0X9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC40	ENST00000397545.9 linkuse as main transcript	c.3424T>C	p.Ser1142Pro	missense_variant	20/20	5	NM_017950.4	ENSP00000380679.4		Q4G0X9-1
CCDC40	ENST00000574799.5 linkuse as main transcript	n.2961T>C		non_coding_transcript_exon_variant	16/16	1

Frequencies

GnomAD3 genomes

AF:

0.00328

AC:

498

AN:

151922

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0115

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000589

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.000910

AC:

225

AN:

247352

Hom.:

AF XY:

0.000616

AC XY:

AN XY:

134726

show subpopulations

Gnomad AFR exome

AF:

0.0122

Gnomad AMR exome

AF:

0.000842

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000713

Gnomad OTH exome

AF:

0.000332

GnomAD4 exome

AF:

0.000397

AC:

580

AN:

1460528

Hom.:

Cov.:

AF XY:

0.000319

AC XY:

232

AN XY:

726602

show subpopulations

Gnomad4 AFR exome

AF:

0.0132

Gnomad4 AMR exome

AF:

0.000806

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000270

Gnomad4 OTH exome

AF:

0.00103

GnomAD4 genome

AF:

0.00328

AC:

498

AN:

152040

Hom.:

Cov.:

AF XY:

0.00284

AC XY:

211

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.0115

Gnomad4 AMR

AF:

0.000850

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000589

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00150

Hom.:

Bravo

AF:

0.00408

ESP6500AA

AF:

0.00709

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.00108

AC:

131

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 04, 2021	This alteration is classified as likely 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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

May 07, 2014

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2024

CCDC40: BP4, BS1 -

Primary ciliary dyskinesia 15

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Aug 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.057

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.037

LIST_S2

Benign

0.38

MetaRNN

Benign

0.0039

MetaSVM

Benign

-0.96

MutationAssessor

Benign

2.0

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.6

REVEL

Benign

0.059

Sift

Uncertain

0.0090

Sift4G

Pathogenic

0.0

Polyphen

0.0010

Vest4

0.062

MVP

0.12

MPC

0.23

ClinPred

0.0082

GERP RS

-5.4

Varity_R

0.16

gMVP

0.35

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