3-180616670-C-A

Variant names:

• chr3-180616670-C-A
• rs61733583
• NM_181426.2:c.2432G>T

Variant summary

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

The NM_181426.2(CCDC39):​c.2432G>T​(p.Arg811Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R811C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CCDC39 NM_181426.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.28
• Publications: 11 publications found

Genes affected

CCDC39 (HGNC:25244): (coiled-coil domain 39 molecular ruler complex subunit) The protein encoded by this gene is involved in the motility of cilia and flagella. The encoded protein is essential for the assembly of dynein regulatory and inner dynein arm complexes, which regulate ciliary beat. Defects in this gene are a cause of primary ciliary dyskinesia type 14 (CILD14). [provided by RefSeq, Jul 2011]

TTC14 (HGNC:24697): (tetratricopeptide repeat domain 14) Predicted to enable nucleic acid binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000145075 (HGNC:):

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181426.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC39	NM_181426.2	MANE Select	c.2432G>T	p.Arg811Leu	missense	Exon 18 of 20	NP_852091.1	Q9UFE4-1
	TTC14	NM_001288582.2		c.1775-710C>A		intron	N/A	NP_001275511.1	Q96N46-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC39	ENST00000476379.6	TSL:2 MANE Select	c.2432G>T	p.Arg811Leu	missense	Exon 18 of 20	ENSP00000417960.2	Q9UFE4-1
	TTC14	ENST00000382584.8	TSL:1	c.1775-710C>A		intron	N/A	ENSP00000372027.4	Q96N46-2
	CCDC39	ENST00000936067.1		c.2339G>T	p.Arg780Leu	missense	Exon 17 of 19	ENSP00000606126.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1438720 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 713688

African (AFR) AF: 0.00 AC: 0 AN: 33110

American (AMR) AF: 0.00 AC: 0 AN: 41292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25620

East Asian (EAS) AF: 0.00 AC: 0 AN: 39120

South Asian (SAS) AF: 0.00 AC: 0 AN: 83660

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51838

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1098894

Other (OTH) AF: 0.00 AC: 0 AN: 59458

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Uncertain	0.077	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.040	T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		3.3
PrimateAI	Benign	0.33	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.21	T
Polyphen		1.0	D
Vest4		0.58
MutPred		0.30		Gain of glycosylation at T816 (P = 0.0038)
MVP		0.78
MPC		0.37
ClinPred		0.99	D
GERP RS		5.1
PromoterAI		-0.012	Neutral
Varity_R		0.32
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.60		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.60		Position offset: -12

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs61733583; hg19: chr3-180334458;