chr17-80086090-G-C

Position:

• chr17-80086090-G-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.2323G>C​(p.Val775Leu) 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 1,461,830 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V775M) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CCDC40 NM_017950.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.64

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]

CCDC40 (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=0.1189889).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC40	NM_017950.4	c.2323G>C	p.Val775Leu	missense_variant	14/20	ENST00000397545.9	NP_060420.2
CCDC40	NM_001243342.2	c.2323G>C	p.Val775Leu	missense_variant	14/18		NP_001230271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC40	ENST00000397545.9	c.2323G>C	p.Val775Leu	missense_variant	14/20	5	NM_017950.4	ENSP00000380679.4
CCDC40	ENST00000574799.5	n.1860G>C		non_coding_transcript_exon_variant	10/16	1
CCDC40	ENST00000374877.7	c.2323G>C	p.Val775Leu	missense_variant	14/18	5		ENSP00000364011.3
CCDC40	ENST00000572253.5	n.950G>C		non_coding_transcript_exon_variant	3/6	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461830 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727214

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.: 32

ExAC AF: 0.00000826 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.063	.;T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.61	T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;M
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.49	N;N
REVEL	Benign	0.031
Sift	Benign	0.29	T;T
Sift4G	Benign	0.30	T;T
Polyphen		0.019	.;B
Vest4		0.16
MutPred		0.25		Gain of catalytic residue at V775 (P = 0.015);Gain of catalytic residue at V775 (P = 0.015);
MVP		0.21
MPC		0.23
ClinPred		0.090	T
GERP RS		2.7
Varity_R		0.041
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs60684213; hg19: chr17-78059889;