chr3-180651533-C-A

Position:

• chr3-180651533-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_181426.2(CCDC39):​c.1035G>T​(p.Arg345Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000511 in 1,368,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000051 (0 hom.)
• Consequence: CCDC39 NM_181426.2 missense, splice_region
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.774

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC39	NM_181426.2	c.1035G>T	p.Arg345Ser	missense_variant, splice_region_variant	9/20	ENST00000476379.6	NP_852091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC39	ENST00000476379.6	c.1035G>T	p.Arg345Ser	missense_variant, splice_region_variant	9/20	2	NM_181426.2	ENSP00000417960.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000220 AC: 3 AN: 136662 Hom.: 0 AF XY: 0.0000278 AC XY: 2 AN XY: 71834

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000129

Gnomad EAS exome AF: 0.000106

Gnomad SAS exome AF: 0.0000580

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000511 AC: 7 AN: 1368960 Hom.: 0 Cov.: 29 AF XY: 0.00000741 AC XY: 5 AN XY: 674758

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000820

Gnomad4 EAS exome AF: 0.0000282

Gnomad4 SAS exome AF: 0.0000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000281

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000189

ExAC AF: 0.00000966 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	0.0087	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.027	T
Eigen	Benign	0.036
Eigen_PC	Benign	0.013
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.7	M
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.22	T
Polyphen		0.82	P
Vest4		0.29
MutPred		0.19		Loss of MoRF binding (P = 0.0105);
MVP		0.89
MPC		0.11
ClinPred		0.64	D
GERP RS		3.1
Varity_R		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.42		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.42		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs770110944; hg19: chr3-180369321;