rs1301657020

chr17-80039865-C-Gchr17-80039865-C-T

Variant summary

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

The NM_017950.4(CCDC40):c.147C>G(p.Ser49Arg) 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 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S49S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CCDC40 NM_017950.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.58

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=0.09254998).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC40	NM_017950.4	c.147C>G	p.Ser49Arg	missense_variant	3/20	ENST00000397545.9
CCDC40	NM_001243342.2	c.147C>G	p.Ser49Arg	missense_variant	3/18
CCDC40	NM_001330508.2	c.147C>G	p.Ser49Arg	missense_variant	3/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC40	ENST00000397545.9	c.147C>G	p.Ser49Arg	missense_variant	3/20	5	NM_017950.4	P2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.00000405 AC: 1 AN: 247062 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134266

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461852 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	0.40
Dann	Benign	0.82
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.52	T;T;T;T;T;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.093	T;T;T;T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.34	N;N;N;N;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.85	N;N;N;N;.;.
REVEL	Benign	0.12
Sift	Benign	0.045	D;D;D;D;.;.
Sift4G	Benign	0.53	T;T;T;T;.;D
Polyphen		0.40, 0.87	.;B;.;P;.;.
Vest4		0.13
MutPred		0.25		Loss of phosphorylation at S49 (P = 0.0169);Loss of phosphorylation at S49 (P = 0.0169);Loss of phosphorylation at S49 (P = 0.0169);Loss of phosphorylation at S49 (P = 0.0169);.;.;
MVP		0.30
MPC		0.23
ClinPred		0.10	T
GERP RS		-2.6
Varity_R		0.078
gMVP		0.059

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: rs1301657020; hg19: chr17-78013664;