17-80095398-G-C

Variant names:

• chr17-80095398-G-C
• rs200958035
• NM_017950.4:c.2968G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017950.4(CCDC40):​c.2968G>C​(p.Asp990His) 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. D990N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: CCDC40 NM_017950.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.79
• Publications: 8 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19284418).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC40	NM_017950.4	c.2968G>C	p.Asp990His	missense_variant	Exon 18 of 20	ENST00000397545.9	NP_060420.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC40	ENST00000397545.9	c.2968G>C	p.Asp990His	missense_variant	Exon 18 of 20	5	NM_017950.4	ENSP00000380679.4
CCDC40	ENST00000574799.5	n.2505G>C		non_coding_transcript_exon_variant	Exon 14 of 16	1
CCDC40	ENST00000572253.5	n.3219G>C		non_coding_transcript_exon_variant	Exon 5 of 6	2
CCDC40	ENST00000575431.1	n.*61G>C		downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000825 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.8
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.12
Sift	Benign	0.079	T
Sift4G	Benign	0.085	T
Vest4		0.41
ClinPred		0.16	T
GERP RS		3.3
Varity_R		0.087
gMVP		0.26
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs200958035; hg19: chr17-78069197;