17-80050200-G-T

Variant names:

• chr17-80050200-G-T
• rs373746597
• NM_017950.4:c.1076G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_017950.4(CCDC40):​c.1076G>T​(p.Arg359Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,458,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R359C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CCDC40 NM_017950.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.92
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 15

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, Laboratory for Molecular Medicine
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autoimmune disease

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000289689 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.76

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC40	NM_017950.4	c.1076G>T	p.Arg359Leu	missense_variant	Exon 7 of 20	ENST00000397545.9	NP_060420.2
CCDC40	NM_001243342.2	c.1076G>T	p.Arg359Leu	missense_variant	Exon 7 of 18		NP_001230271.1
CCDC40	NM_001330508.2	c.1076G>T	p.Arg359Leu	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.1076G>T	p.Arg359Leu	missense_variant	Exon 7 of 20	5	NM_017950.4	ENSP00000380679.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458912 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 725762

African (AFR) AF: 0.00 AC: 0 AN: 33420

American (AMR) AF: 0.00 AC: 0 AN: 44512

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26080

East Asian (EAS) AF: 0.00 AC: 0 AN: 39634

South Asian (SAS) AF: 0.00 AC: 0 AN: 86000

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52674

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4982

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111410

Other (OTH) AF: 0.00 AC: 0 AN: 60200

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.59	.;D;.;.
Eigen	Benign	0.15
Eigen_PC	Benign	0.081
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.83	T;T;T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.76	D;D;D;D
MetaSVM	Benign	-0.45	T
MutationAssessor	Pathogenic	3.0	M;M;M;M
PhyloP100		6.9
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-5.2	D;D;D;D
REVEL	Benign	0.28
Sift	Benign	0.065	T;T;D;D
Sift4G	Benign	0.14	T;T;T;T
Polyphen		0.042, 1.0	.;B;.;D
Vest4		0.84
MutPred		0.30		Loss of MoRF binding (P = 0.0659);Loss of MoRF binding (P = 0.0659);Loss of MoRF binding (P = 0.0659);Loss of MoRF binding (P = 0.0659);
MVP		0.68
MPC		0.30
ClinPred		0.91	D
GERP RS		4.8
Varity_R		0.37
gMVP		0.55
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

dbSNP: rs373746597; hg19: chr17-78023999;