rs201064110

chr17-80082018-A-Cchr17-80082018-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_017950.4(CCDC40):c.1949A>C(p.Asn650Thr) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N650S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 26)
• Consequence: CCDC40 NM_017950.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.393

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.045072585).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC40	NM_017950.4	c.1949A>C	p.Asn650Thr	missense_variant	12/20	ENST00000397545.9
CCDC40	NM_001243342.2	c.1949A>C	p.Asn650Thr	missense_variant	12/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC40	ENST00000397545.9	c.1949A>C	p.Asn650Thr	missense_variant	12/20	5	NM_017950.4	P2
CCDC40	ENST00000574799.5	n.1486A>C		non_coding_transcript_exon_variant	8/16	1
CCDC40	ENST00000374877.7	c.1949A>C	p.Asn650Thr	missense_variant	12/18	5		A2
CCDC40	ENST00000572253.5	n.576A>C		non_coding_transcript_exon_variant	1/6	2

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 26

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 06, 2017

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with CCDC40-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with threonine at codon 650 of the CCDC40 protein (p.Asn650Thr). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and threonine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	9.3
Dann	Benign	0.90
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.62	T;T
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.045	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.99	N;N
REVEL	Benign	0.050
Sift	Benign	0.51	T;T
Sift4G	Benign	0.57	T;T
Polyphen		0.11	.;B
Vest4		0.21
MutPred		0.21		Gain of phosphorylation at T646 (P = 0.0923);Gain of phosphorylation at T646 (P = 0.0923);
MVP		0.061
MPC		0.20
ClinPred		0.048	T
GERP RS		-5.2
Varity_R		0.038
gMVP		0.072

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

Other links and lift over

dbSNP: rs201064110; hg19: chr17-78055817;