dbSNP rs1555889343: 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017950.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CCDC40	NM_017950.4	MANE Select	c.83A>G	p.Glu28Gly	missense	Exon 2 of 20	NP_060420.2
CCDC40	NM_001243342.2		c.83A>G	p.Glu28Gly	missense	Exon 2 of 18	NP_001230271.1
CCDC40	NM_001330508.2		c.83A>G	p.Glu28Gly	missense	Exon 2 of 11	NP_001317437.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CCDC40	ENST00000397545.9	TSL:5 MANE Select	c.83A>G	p.Glu28Gly	missense	Exon 2 of 20	ENSP00000380679.4
CCDC40	ENST00000374876.4	TSL:1	c.83A>G	p.Glu28Gly	missense	Exon 2 of 9	ENSP00000364010.4
CCDC40	ENST00000374877.7	TSL:5	c.83A>G	p.Glu28Gly	missense	Exon 2 of 18	ENSP00000364011.3

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 v4.9

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

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.051

LIST_S2

Benign

0.45

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.10

MetaSVM

Benign

-0.63

MutationAssessor

Benign

0.55

PhyloP100

-0.12

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.3

REVEL

Benign

0.055

Sift

Uncertain

0.010

Sift4G

Uncertain

0.052

Polyphen

0.18

Vest4

0.18

MutPred

0.17

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over