rs201586263

Variant names:

• chr3-180619912-T-C
• rs201586263
• NM_181426.2:c.2057A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_181426.2(CCDC39):​c.2057A>G​(p.Asn686Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000386 in 1,610,642 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00039 (3 hom.)
• Consequence: CCDC39 NM_181426.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 1.88
• Publications: 2 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.035393506).
• BP6: Variant 3-180619912-T-C is Benign according to our data. Variant chr3-180619912-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 220134.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR gene

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.2057A>G	p.Asn686Ser	missense	Exon 15 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.2057A>G	p.Asn686Ser	missense	Exon 15 of 20	ENSP00000417960.2	Q9UFE4-1
	CCDC39	ENST00000936067.1		c.1964A>G	p.Asn655Ser	missense	Exon 14 of 19	ENSP00000606126.1
	CCDC39	ENST00000651046.1		c.1865A>G	p.Asn622Ser	missense	Exon 14 of 19	ENSP00000499175.1	A0A494C1Q3

Frequencies

GnomAD3 genomes AF: 0.000323 AC: 49 AN: 151774 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000969

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000527

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000530

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000269 AC: 66 AN: 245400 AF XY: 0.000315

Gnomad AFR exome AF: 0.000131

Gnomad AMR exome AF: 0.0000882

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000306

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000393 AC: 573 AN: 1458750 Hom.: 3 Cov.: 30 AF XY: 0.000405 AC XY: 294 AN XY: 725594

African (AFR) AF: 0.0000599 AC: 2 AN: 33386

American (AMR) AF: 0.000158 AC: 7 AN: 44416

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26028

East Asian (EAS) AF: 0.00 AC: 0 AN: 39604

South Asian (SAS) AF: 0.000850 AC: 73 AN: 85890

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53012

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5754

European-Non Finnish (NFE) AF: 0.000421 AC: 468 AN: 1110424

Other (OTH) AF: 0.000365 AC: 22 AN: 60236

GnomAD4 genome AF: 0.000323 AC: 49 AN: 151892 Hom.: 0 Cov.: 30 AF XY: 0.000296 AC XY: 22 AN XY: 74248

African (AFR) AF: 0.0000966 AC: 4 AN: 41416

American (AMR) AF: 0.000527 AC: 8 AN: 15190

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

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

European-Non Finnish (NFE) AF: 0.000530 AC: 36 AN: 67954

Other (OTH) AF: 0.00 AC: 0 AN: 2102

Alfa AF: 0.000340 Hom.: 0

Bravo AF: 0.000298

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000274 AC: 1

ESP6500EA AF: 0.000368 AC: 3

ExAC AF: 0.000232 AC: 28

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Primary ciliary dyskinesia (2)
-	1	-	not provided (1)
-	1	-	Primary ciliary dyskinesia 14 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Benign	0.00092	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.035	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.57	N
PhyloP100		1.9
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.26
Sift	Benign	0.35	T
Sift4G	Benign	1.0	T
Polyphen		0.0070	B
Vest4		0.22
MVP		0.45
MPC		0.045
ClinPred		0.0065	T
GERP RS		1.8
Varity_R		0.046
Mutation Taster		=98/2	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: rs201586263; hg19: chr3-180337700; COSMIC: COSV56477703; COSMIC: COSV56477703;