rs116795025

Positions:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2BP4_StrongBP6_Very_StrongBS1

The NM_017950.4(CCDC40):c.1132G>A(p.Ala378Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000578 in 1,582,168 control chromosomes in the GnomAD database, including 1 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 0.0032 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00030 ( 0 hom. )

Consequence

CCDC40
NM_017950.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.178

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0043277442).

BP6

Variant 17-80050256-G-A is Benign according to our data. Variant chr17-80050256-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 260948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00322 (490/152282) while in subpopulation AFR AF= 0.0114 (474/41562). AF 95% confidence interval is 0.0106. There are 1 homozygotes in gnomad4. There are 232 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CCDC40	NM_017950.4 linkuse as main transcript	c.1132G>A	p.Ala378Thr	missense_variant	7/20	ENST00000397545.9	NP_060420.2
CCDC40	NM_001243342.2 linkuse as main transcript	c.1132G>A	p.Ala378Thr	missense_variant	7/18		NP_001230271.1
CCDC40	NM_001330508.2 linkuse as main transcript	c.1132G>A	p.Ala378Thr	missense_variant	7/11		NP_001317437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC40	ENST00000397545.9 linkuse as main transcript	c.1132G>A	p.Ala378Thr	missense_variant	7/20	5	NM_017950.4	ENSP00000380679	P2	Q4G0X9-1
	ENST00000695611.1 linkuse as main transcript	n.1432-2737C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00321

AC:

488

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0114

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:

0.00

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000675

AC:

129

AN:

191060

Hom.:

AF XY:

0.000575

AC XY:

AN XY:

104270

show subpopulations

Gnomad AFR exome

AF:

0.0113

Gnomad AMR exome

AF:

0.000321

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000383

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000399

GnomAD4 exome

AF:

0.000297

AC:

425

AN:

1429886

Hom.:

Cov.:

AF XY:

0.000241

AC XY:

171

AN XY:

709098

show subpopulations

Gnomad4 AFR exome

AF:

0.0115

Gnomad4 AMR exome

AF:

0.000379

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000362

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000273

Gnomad4 OTH exome

AF:

0.000491

GnomAD4 genome

AF:

0.00322

AC:

490

AN:

152282

Hom.:

Cov.:

AF XY:

0.00312

AC XY:

232

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.0114

Gnomad4 AMR

AF:

0.000849

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000209

Hom.:

Bravo

AF:

0.00363

ESP6500AA

AF:

0.0124

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000776

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

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 20, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 16, 2018	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 specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 06, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.72

CADD

Benign

3.6

DANN

Benign

0.91

DEOGEN2

Benign

0.062

.;T;.;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.091

LIST_S2

Benign

0.60

T;T;T;T

MetaRNN

Benign

0.0043

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

L;L;L;L

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.70

N;N;N;N

REVEL

Benign

0.033

Sift

Benign

0.52

T;T;T;T

Sift4G

Benign

0.36

T;T;T;T

Polyphen

0.045, 0.79

.;B;.;P

Vest4

0.23

MVP

0.067

MPC

0.17

ClinPred

0.0026

GERP RS

-1.7

Varity_R

0.025

gMVP

0.031

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