3-180663940-C-G

Variant names:

• chr3-180663940-C-G
• rs376716008
• NM_181426.2:c.137G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_181426.2(CCDC39):​c.137G>C​(p.Arg46Pro) 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 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R46H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CCDC39 NM_181426.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.137
• Publications: 0 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]

CCDC39 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 14

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000145075 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10459265).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC39	NM_181426.2	MANE Select	c.137G>C	p.Arg46Pro	missense	Exon 2 of 20	NP_852091.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC39	ENST00000476379.6	TSL:2 MANE Select	c.137G>C	p.Arg46Pro	missense	Exon 2 of 20	ENSP00000417960.2
	CCDC39	ENST00000651046.1		c.137G>C	p.Arg46Pro	missense	Exon 2 of 19	ENSP00000499175.1
	ENSG00000145075	ENST00000471307.6	TSL:3	n.574G>C		non_coding_transcript_exon	Exon 6 of 7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	7.7
DANN	Benign	0.95
DEOGEN2	Benign	0.0022	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.9	M
PhyloP100		-0.14
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.78	N
REVEL	Uncertain	0.42
Sift	Benign	0.23	T
Sift4G	Benign	0.081	T
Polyphen		0.41	B
Vest4		0.52
MutPred		0.23		Gain of glycosylation at Y48 (P = 0.046)
MVP		0.64
MPC		0.15
ClinPred		0.16	T
GERP RS		-2.5
Varity_R		0.22
Mutation Taster		=99/1	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: rs376716008; hg19: chr3-180381728;