rs199786478

Positions:

• chr17-80081697-T-A
• chr17-80081697-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017950.4(CCDC40):​c.1714T>A​(p.Cys572Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CCDC40 NM_017950.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.30

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.113734215).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC40	NM_017950.4	c.1714T>A	p.Cys572Ser	missense_variant	11/20	ENST00000397545.9	NP_060420.2
CCDC40	NM_001243342.2	c.1714T>A	p.Cys572Ser	missense_variant	11/18		NP_001230271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC40	ENST00000397545.9	c.1714T>A	p.Cys572Ser	missense_variant	11/20	5	NM_017950.4	ENSP00000380679	P2
CCDC40	ENST00000574799.5	n.1251T>A		non_coding_transcript_exon_variant	7/16	1
CCDC40	ENST00000374877.7	c.1714T>A	p.Cys572Ser	missense_variant	11/18	5		ENSP00000364011	A2
CCDC40	ENST00000572253.5	n.255T>A		non_coding_transcript_exon_variant	1/6	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461848 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	16
DANN	Benign	0.83
DEOGEN2	Benign	0.40	.;T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.56	T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	0.51	N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-5.1	D;D
REVEL	Benign	0.061
Sift	Benign	0.37	T;T
Sift4G	Benign	0.16	T;T
Polyphen		0.037	.;B
Vest4		0.28
MutPred		0.35		Loss of catalytic residue at L573 (P = 0.0135);Loss of catalytic residue at L573 (P = 0.0135);
MVP		0.28
MPC		0.23
ClinPred		0.25	T
GERP RS		3.1
Varity_R		0.26
gMVP		0.26

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: rs199786478; hg19: chr17-78055496;