rs750628862

Variant names:

• chr17-80040073-C-A
• rs750628862
• NM_017950.4:c.355C>A

Variant summary

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

The NM_017950.4(CCDC40):​c.355C>A​(p.Pro119Thr) 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 1,461,798 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CCDC40 NM_017950.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.262

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=0.1008949).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC40	NM_017950.4	c.355C>A	p.Pro119Thr	missense_variant	Exon 3 of 20	ENST00000397545.9	NP_060420.2
CCDC40	NM_001243342.2	c.355C>A	p.Pro119Thr	missense_variant	Exon 3 of 18		NP_001230271.1
CCDC40	NM_001330508.2	c.355C>A	p.Pro119Thr	missense_variant	Exon 3 of 11		NP_001317437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC40	ENST00000397545.9	c.355C>A	p.Pro119Thr	missense_variant	Exon 3 of 20	5	NM_017950.4	ENSP00000380679.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248678 Hom.: 0 AF XY: 0.00000741 AC XY: 1 AN XY: 135000

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: 1461798 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727200

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.: 32

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1

Sep 01, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline with threonine at codon 119 of the CCDC40 protein (p.Pro119Thr). The proline residue is weakly conserved and there is a small physicochemical difference between proline and threonine. This variant is present in population databases (rs750628862, ExAC 0.009%). This variant has not been reported in the literature in individuals affected with CCDC40-related conditions. 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. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	1.4
DANN	Benign	0.47
DEOGEN2	Benign	0.061	.;T;.;.;.;.
Eigen	Benign	-0.82
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.55	T;T;T;T;T;T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.10	T;T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.69	N;N;N;N;.;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.80	N;N;N;N;.;.
REVEL	Benign	0.079
Sift	Benign	0.065	T;T;D;D;.;.
Sift4G	Benign	0.42	T;T;T;T;D;T
Polyphen		0.34, 1.0	.;B;.;D;.;.
Vest4		0.17
MutPred		0.30		Gain of phosphorylation at P119 (P = 0.0175);Gain of phosphorylation at P119 (P = 0.0175);Gain of phosphorylation at P119 (P = 0.0175);Gain of phosphorylation at P119 (P = 0.0175);.;.;
MVP		0.32
MPC		0.22
ClinPred		0.073	T
GERP RS		0.14
Varity_R		0.065
gMVP		0.23

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: rs750628862; hg19: chr17-78013872;