NM_181426.2:c.1363-3delC

Variant names:

• chr3-180647245-TG-T
• rs551191744
• NM_181426.2:c.1363-3delC

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_181426.2(CCDC39):​c.1363-3delC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000843 in 1,558,374 control chromosomes in the GnomAD database, including 3 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00073 (3 hom.)
• Consequence: CCDC39 NM_181426.2 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 3.55
• Publications: 3 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.

• BP6: Variant 3-180647245-TG-T is Benign according to our data. Variant chr3-180647245-TG-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 242168.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00193 (288/149096) while in subpopulation AMR AF = 0.00555 (82/14764). AF 95% confidence interval is 0.00458. There are 0 homozygotes in GnomAd4. There are 156 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR,AD 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.1363-3delC		splice_region 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.1363-3delC		splice_region intron	N/A	ENSP00000417960.2	Q9UFE4-1
	CCDC39	ENST00000936067.1		c.1270-3delC		splice_region intron	N/A	ENSP00000606126.1
	CCDC39	ENST00000651046.1		c.1171-3delC		splice_region intron	N/A	ENSP00000499175.1	A0A494C1Q3

Frequencies

GnomAD3 genomes AF: 0.00195 AC: 290 AN: 148984 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00364

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00556

Gnomad ASJ AF: 0.000292

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000211

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0196

Gnomad NFE AF: 0.000614

Gnomad OTH AF: 0.00493

GnomAD2 exomes AF: 0.00124 AC: 215 AN: 173520 AF XY: 0.00123

Gnomad AFR exome AF: 0.00383

Gnomad AMR exome AF: 0.00455

Gnomad ASJ exome AF: 0.000530

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000113

Gnomad NFE exome AF: 0.000829

Gnomad OTH exome AF: 0.00211

GnomAD4 exome AF: 0.000727 AC: 1025 AN: 1409278 Hom.: 3 Cov.: 30 AF XY: 0.000753 AC XY: 526 AN XY: 698472

African (AFR) AF: 0.00447 AC: 138 AN: 30886

American (AMR) AF: 0.00394 AC: 126 AN: 31940

Ashkenazi Jewish (ASJ) AF: 0.000573 AC: 14 AN: 24434

East Asian (EAS) AF: 0.00 AC: 0 AN: 38920

South Asian (SAS) AF: 0.0000648 AC: 5 AN: 77218

European-Finnish (FIN) AF: 0.0000392 AC: 2 AN: 50956

Middle Eastern (MID) AF: 0.00681 AC: 38 AN: 5578

European-Non Finnish (NFE) AF: 0.000534 AC: 583 AN: 1091036

Other (OTH) AF: 0.00204 AC: 119 AN: 58310

GnomAD4 genome AF: 0.00193 AC: 288 AN: 149096 Hom.: 0 Cov.: 32 AF XY: 0.00215 AC XY: 156 AN XY: 72722

African (AFR) AF: 0.00359 AC: 147 AN: 41000

American (AMR) AF: 0.00555 AC: 82 AN: 14764

Ashkenazi Jewish (ASJ) AF: 0.000292 AC: 1 AN: 3430

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.000212 AC: 1 AN: 4728

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10034

Middle Eastern (MID) AF: 0.0211 AC: 6 AN: 284

European-Non Finnish (NFE) AF: 0.000614 AC: 41 AN: 66756

Other (OTH) AF: 0.00487 AC: 10 AN: 2052

Alfa AF: 0.000656 Hom.: 0

Bravo AF: 0.00253

Asia WGS AF: 0.000869 AC: 3 AN: 3468

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.5
Mutation Taster		=9/91	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs551191744; hg19: chr3-180365033;