rs397515392

Variant names:

• chr3-180661860-C-G
• rs397515392
• NM_181426.2:c.357+1G>C

Your query was ambiguous. Multiple possible variants found:

• chr3-180661860-C-G
• chr3-180661860-C-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1_Moderate PP5_Very_Strong

The NM_181426.2(CCDC39):​c.357+1G>C variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.000141 in 1,577,022 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: CCDC39 NM_181426.2 splice_donor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 6.68
• Publications: 5 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.052016985 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PP5: Variant 3-180661860-C-G is Pathogenic according to our data. Variant chr3-180661860-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 31067.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.357+1G>C		splice_donor intron	N/A	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.357+1G>C		splice_donor intron	N/A	ENSP00000417960.2	Q9UFE4-1
	CCDC39	ENST00000936067.1		c.357+1G>C		splice_donor intron	N/A	ENSP00000606126.1
	CCDC39	ENST00000651046.1		c.357+1G>C		splice_donor intron	N/A	ENSP00000499175.1	A0A494C1Q3

Frequencies

GnomAD3 genomes AF: 0.0000658 AC: 10 AN: 151920 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000155 AC: 31 AN: 199632 AF XY: 0.000197

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000351

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000235

Gnomad OTH exome AF: 0.000194

GnomAD4 exome AF: 0.000149 AC: 212 AN: 1425102 Hom.: 0 Cov.: 30 AF XY: 0.000153 AC XY: 108 AN XY: 705476

African (AFR) AF: 0.00 AC: 0 AN: 32818

American (AMR) AF: 0.000332 AC: 13 AN: 39180

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25526

East Asian (EAS) AF: 0.00 AC: 0 AN: 38454

South Asian (SAS) AF: 0.00 AC: 0 AN: 81286

European-Finnish (FIN) AF: 0.0000389 AC: 2 AN: 51414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.000167 AC: 182 AN: 1091598

Other (OTH) AF: 0.000254 AC: 15 AN: 59104

GnomAD4 genome AF: 0.0000658 AC: 10 AN: 151920 Hom.: 0 Cov.: 32 AF XY: 0.0000674 AC XY: 5 AN XY: 74198

African (AFR) AF: 0.0000242 AC: 1 AN: 41388

American (AMR) AF: 0.000131 AC: 2 AN: 15250

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67922

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.000122 Hom.: 0

Bravo AF: 0.000110

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000117 AC: 14

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Primary ciliary dyskinesia 14 (6)
2	-	-	not provided (2)
2	-	-	Primary ciliary dyskinesia (2)
1	-	-	CCDC39-related disorder (1)
1	-	-	Infertility disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	26
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		6.7
GERP RS		5.3
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.90
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.97		Position offset: 1

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

Other links and lift over

dbSNP: rs397515392; hg19: chr3-180379648;