3-180648168-G-T

Variant names:

• chr3-180648168-G-T
• rs6769457
• NM_181426.2:c.1359C>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_181426.2(CCDC39):​c.1359C>A​(p.Ser453Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000429 in 1,607,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S453S) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000046 (0 hom.)
• Consequence: CCDC39 NM_181426.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.458
• Publications: 9 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: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000145075 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.29833502).

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.1359C>A	p.Ser453Arg	missense	Exon 10 of 20	NP_852091.1	Q9UFE4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC39	ENST00000476379.6	TSL:2 MANE Select	c.1359C>A	p.Ser453Arg	missense	Exon 10 of 20	ENSP00000417960.2	Q9UFE4-1
	CCDC39	ENST00000936067.1		c.1266C>A	p.Ser422Arg	missense	Exon 9 of 19	ENSP00000606126.1
	CCDC39	ENST00000651046.1		c.1167C>A	p.Ser389Arg	missense	Exon 9 of 19	ENSP00000499175.1	A0A494C1Q3

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151852 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000203 AC: 5 AN: 246654 AF XY: 0.0000374

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000280

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000460 AC: 67 AN: 1455910 Hom.: 0 Cov.: 29 AF XY: 0.0000483 AC XY: 35 AN XY: 724422

African (AFR) AF: 0.00 AC: 0 AN: 33260

American (AMR) AF: 0.00 AC: 0 AN: 44552

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00164 AC: 65 AN: 39580

South Asian (SAS) AF: 0.00 AC: 0 AN: 85978

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53244

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5628

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107460

Other (OTH) AF: 0.0000333 AC: 2 AN: 60124

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151970 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74286

African (AFR) AF: 0.00 AC: 0 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10558

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67938

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.00 Hom.: 19012

ExAC AF: 0.0000248 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Primary ciliary dyskinesia 14 (2)
-	1	-	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0035	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.52
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.45	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.46
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.23
Sift	Benign	0.039	D
Sift4G	Benign	0.31	T
Polyphen		0.55	P
Vest4		0.35
MutPred		0.34		Gain of MoRF binding (P = 0.0181)
MVP		0.79
MPC		0.078
ClinPred		0.074	T
GERP RS		1.5
Varity_R		0.089
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs6769457; hg19: chr3-180365956;