Genetic Variant NM_017950.4:c.3030T>A (chr17-80097253-T-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_017950.4(CCDC40):c.3030T>A(p.Asp1010Glu) 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. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1010N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

CCDC40
NM_017950.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.368

Publications

29 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:

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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=0.016174018).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC40	NM_017950.4	MANE Select	c.3030T>A	p.Asp1010Glu	missense	Exon 19 of 20	NP_060420.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CCDC40	ENST00000397545.9	TSL:5 MANE Select	c.3030T>A	p.Asp1010Glu	missense	Exon 19 of 20	ENSP00000380679.4
CCDC40	ENST00000574799.5	TSL:1	n.2567T>A		non_coding_transcript_exon	Exon 15 of 16
CCDC40	ENST00000572253.5	TSL:2	n.3281T>A		non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

86886

ExAC

AF:

0.00000827

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.51

(source)

DANN

Benign

0.52

DEOGEN2

Benign

0.027

Eigen

Benign

-2.1

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.073

LIST_S2

Benign

0.40

M_CAP

Benign

0.0022

MetaRNN

Benign

0.016

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.7

PhyloP100

-0.37

PrimateAI

Benign

0.33

PROVEAN

Benign

1.7

REVEL

Benign

0.073

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.051

MutPred

0.14

Loss of MoRF binding (P = 0.1147)

MVP

0.030

MPC

0.16

ClinPred

0.030

GERP RS

-1.2

Varity_R

0.030

gMVP

0.028

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Computational scores

Splicing

Publications

Other links and lift over