17-80065523-G-T

Position:

chr17-80065523-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_017950.4(CCDC40):c.1479G>T(p.Arg493Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000207 in 1,613,156 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 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 0.00031 ( 0 hom., cov: 29)

Exomes 𝑓: 0.00020 ( 1 hom. )

Consequence

CCDC40
NM_017950.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 2.10

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15898114).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CCDC40	NM_017950.4 linkuse as main transcript	c.1479G>T	p.Arg493Ser	missense_variant	10/20	ENST00000397545.9
LOC124904074	XR_007065931.1 linkuse as main transcript	n.305+5709C>A		intron_variant, non_coding_transcript_variant
CCDC40	NM_001243342.2 linkuse as main transcript	c.1479G>T	p.Arg493Ser	missense_variant	10/18
CCDC40	NM_001330508.2 linkuse as main transcript	c.1479G>T	p.Arg493Ser	missense_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC40	ENST00000397545.9 linkuse as main transcript	c.1479G>T	p.Arg493Ser	missense_variant	10/20	5	NM_017950.4	P2	Q4G0X9-1
	ENST00000695611.1 linkuse as main transcript	n.313+5709C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.000309

AC:

AN:

152064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000125

AC:

AN:

248806

Hom.:

AF XY:

0.000104

AC XY:

AN XY:

135262

show subpopulations

Gnomad AFR exome

AF:

0.000130

Gnomad AMR exome

AF:

0.000232

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000169

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.000196

AC:

287

AN:

1460974

Hom.:

Cov.:

AF XY:

0.000195

AC XY:

142

AN XY:

726828

show subpopulations

Gnomad4 AFR exome

AF:

0.000478

Gnomad4 AMR exome

AF:

0.000291

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000210

Gnomad4 OTH exome

AF:

0.000315

GnomAD4 genome

AF:

0.000309

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000129

Hom.:

Bravo

AF:

0.000321

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000235

AC:

ESP6500EA

AF:

0.000354

AC:

ExAC

AF:

0.000149

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 15

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Mar 29, 2021	CCDC40 c.1479G>T (rs201739201) is rare (<0.1%) in a large population dataset (gnomAD: 37/280170 total alleles; 0.013%; 1 homozygote) and has not been reported in the literature, to our knowledge. There is an entry for this variant in ClinVar (Variation ID: 525439). Of three bioinformatics tools queried, one predicts that the substitution would be damaging, while two predict that it would be tolerated. The arginine residue at this position is not highly evolutionarily conserved in the species assessed. We consider the clinical significance of c.1479G>T to be uncertain at this time. -
Uncertain significance, 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, 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. -

CCDC40-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 08, 2023

The CCDC40 c.1479G>T variant is predicted to result in the amino acid substitution p.Arg493Ser. This variant was reported in an individual with primary ciliary dyskinesia; however, it's zygosity was not specified and it is unclear if another CCDC40 variant was present, in addition, this individual also carried variants in DNAH5 and DNAH8 genes (Br-12, Table S4 and Table S5 - Olm et al. 2019. PubMed ID: 31213628). This variant is reported in 0.023% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-78039322-G-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Primary ciliary dyskinesia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.23

.;T;.

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.76

T;T;T

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.16

T;T;T

MetaSVM

Uncertain

-0.18

MutationAssessor

Benign

1.6

L;L;L

MutationTaster

Benign

0.59

D;D;D;D

PrimateAI

Benign

0.29

PROVEAN

Benign

-2.2

N;N;N

REVEL

Benign

0.19

Sift

Uncertain

0.0050

D;D;D

Sift4G

Benign

0.063

T;T;D

Polyphen

0.70

.;P;.

Vest4

0.46

MutPred

0.29

Loss of MoRF binding (P = 0.0298);Loss of MoRF binding (P = 0.0298);Loss of MoRF binding (P = 0.0298);

MVP

0.68

MPC

0.29

ClinPred

0.10

GERP RS

2.8

Varity_R

0.19

gMVP

0.22

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