Genetic Variant CCDC40:p.Glu28Gly (chr17-80038176-A-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6_Moderate

The NM_017950.4(CCDC40):c.83A>G(p.Glu28Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 32)

Consequence

CCDC40
NM_017950.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.122

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

primary ciliary dyskinesia 15
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, Laboratory for Molecular Medicine
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autoimmune disease
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

CCDC40 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.100384355).

BP6

Variant 17-80038176-A-G is Benign according to our data. Variant chr17-80038176-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 505068.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC40	NM_017950.4 link	c.83A>G	p.Glu28Gly	missense_variant	Exon 2 of 20	ENST00000397545.9	NP_060420.2	Q4G0X9-1
CCDC40	NM_001243342.2 link	c.83A>G	p.Glu28Gly	missense_variant	Exon 2 of 18		NP_001230271.1	Q4G0X9-2
CCDC40	NM_001330508.2 link	c.83A>G	p.Glu28Gly	missense_variant	Exon 2 of 11		NP_001317437.1	Q4G0X9-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC40	ENST00000397545.9 link	c.83A>G	p.Glu28Gly	missense_variant	Exon 2 of 20	5	NM_017950.4	ENSP00000380679.4		Q4G0X9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Jun 07, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Glu28Gly of CCDC40: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. Of note, four mammals have a glycine (Gly) at this position despite high nearby amino acid con servation. In addition, computational prediction tools do not suggest a high lik elihood of impact to the protein. This variant was absent from large population studies. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.060

BayesDel_noAF

Benign

-0.32

CADD

Benign

6.3

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.049

.;T;.;.

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.051

LIST_S2

Benign

0.45

T;T;T;T

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.10

T;T;T;T

MetaSVM

Benign

-0.63

MutationAssessor

Benign

0.55

N;N;N;N

PhyloP100

-0.12

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.3

N;N;N;N

REVEL

Benign

0.055

Sift

Uncertain

0.010

D;D;D;D

Sift4G

Uncertain

0.052

T;D;D;D

Polyphen

0.18, 0.87

.;B;.;P

Vest4

0.18

MutPred

0.17

Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);

MVP

0.52

MPC

0.24

ClinPred

0.25

GERP RS

2.2

Varity_R

0.058

gMVP

0.15

Mutation Taster

=91/9

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over