17-80050256-G-C

Variant names:

• chr17-80050256-G-C
• rs116795025
• NM_017950.4:c.1132G>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.1132G>C​(p.Ala378Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000699 in 1,429,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: CCDC40 NM_017950.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.178

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]

ENSG00000289689 (HGNC:):

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=0.120565).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC40	NM_017950.4	c.1132G>C	p.Ala378Pro	missense_variant	Exon 7 of 20	ENST00000397545.9	NP_060420.2
CCDC40	NM_001243342.2	c.1132G>C	p.Ala378Pro	missense_variant	Exon 7 of 18		NP_001230271.1
CCDC40	NM_001330508.2	c.1132G>C	p.Ala378Pro	missense_variant	Exon 7 of 11		NP_001317437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC40	ENST00000397545.9	c.1132G>C	p.Ala378Pro	missense_variant	Exon 7 of 20	5	NM_017950.4	ENSP00000380679.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000523 AC: 1 AN: 191060 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 104270

Gnomad AFR exome AF: 0.0000969

Gnomad AMR exome AF: 0.00

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: 6.99e-7 AC: 1 AN: 1429886 Hom.: 0 Cov.: 34 AF XY: 0.00000141 AC XY: 1 AN XY: 709098

Gnomad4 AFR exome AF: 0.0000307

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ExAC AF: 0.00000843 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	4.0
DANN	Benign	0.95
DEOGEN2	Benign	0.14	.;T;.;.
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.72	T;T;T;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.9	M;M;M;M
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.1	N;N;N;N
REVEL	Benign	0.098
Sift	Benign	0.27	T;T;T;T
Sift4G	Benign	0.20	T;T;T;T
Polyphen		0.76, 1.0	.;P;.;D
Vest4		0.32
MutPred		0.27		Gain of glycosylation at A378 (P = 0.0276);Gain of glycosylation at A378 (P = 0.0276);Gain of glycosylation at A378 (P = 0.0276);Gain of glycosylation at A378 (P = 0.0276);
MVP		0.21
MPC		0.43
ClinPred		0.067	T
GERP RS		-1.7
Varity_R		0.13
gMVP		0.30

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: rs116795025; hg19: chr17-78024055;