3-180644119-C-T

Variant names:

• chr3-180644119-C-T
• rs753580394
• NM_181426.2:c.1665+1G>A

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+8 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 8 classification points (ACMG Germline Pathogenicity v2019). PVS1_ModeratePM2PP5_Strong

The NM_181426.2(CCDC39):c.1665+1G>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. This is a canonical splice-site variant (loss-of-function). The variant allele was found at a cumulative frequency of 0.0000159 (AC=22) in the gnomAD database across 1,385,634 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000134. In-silico predictor (BayesDel (noAF)) classifies this variant as likely damaging/oncogenic. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: CCDC39 NM_181426.2 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.86
• Publications: 0 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: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000145075 (HGNC:):

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_pathogenic. The variant received 8 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PVS1Null variant in LOF gene		In-frame splice: disease mechanism, limited domain evidence — moderate (PVS1 downgraded to PM); Splice donor variant predicted to cause an in-frame change; loss of function is a known disease mechanism, but domain evidence is limited.
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000134 — very rare for AD+AR gene (base 0.0001, raised to 0.000466 by highest known P/LP ClinVar AF 0.000466) — PM2 moderate.
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_181426.2. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CCDC39 NM_181426.2	MANE Select	c.1665+1G>A	splice_donorintron	Intron 12 of 19	Prot: NP_852091.1 UniProt:

CCDC39 NM_181426.2

MANE Select

HGVSc / HGVSpc.1665+1G>A

Exon rankIntron 12 of 19

splice_donorintron

Prot: NP_852091.1UniProt: Q9UFE4-1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CCDC39 ENST00000476379.6	TSL:2MANE Select	c.1665+1G>A	splice_donorintron	Intron 12 of 19	Prot: ENSP00000417960.2 UniProt:
	CCDC39 ENST00000936067.1		c.1572+1G>A	splice_donorintron	Intron 11 of 18	Prot: ENSP00000606126.1 UniProt:
	CCDC39 ENST00000651046.1		c.1473+1G>A	splice_donorintron	Intron 11 of 18	Prot: ENSP00000499175.1 UniProt:

CCDC39 ENST00000476379.6

TSL:2MANE Select

HGVSc / HGVSpc.1665+1G>A

Exon rankIntron 12 of 19

splice_donorintron

Prot: ENSP00000417960.2UniProt: Q9UFE4-1

CCDC39 ENST00000936067.1

HGVSc / HGVSpc.1572+1G>A

Exon rankIntron 11 of 18

splice_donorintron

Prot: ENSP00000606126.1UniProt: A0ACI8TUU7

CCDC39 ENST00000651046.1

HGVSc / HGVSpc.1473+1G>A

Exon rankIntron 11 of 18

splice_donorintron

Prot: ENSP00000499175.1UniProt: A0A494C1Q3

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD2 exomes	AF: 0.00000676	AC:1	Hom:	AN:147874	Cov:
GnomAD4 exome	AF: 0.0000159	AC:22	Hom:0	AN:1385634	Cov:28
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
TOPMed (Bravo)	AF: 0.00000378	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:13470	Cov:

Showing 6 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.00	0	28054	0.0000700	2	28584
SCHEMA(Schizophrenia)	0.00	0	94466	0.0000121	2	165782

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Primary ciliary dyskinesia (2)
1	-	-	Respiratory ciliopathies including non-CF bronchiectasis (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	32
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	28
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
GPN-Star LLR	N/A	-4.2
GPN-Star score	N/A	4.2
Mutation Taster	N/A	0/100	disease causing (ClinVar)
PhyloP100	Uncertain	4.9

Showing 12 of 12 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
DS_DG_spliceai	Uncertain	0.37	Position offset: 12
DS_DL_spliceai	Pathogenic	0.99	Position offset: 1
Pangolin (max)	Pathogenic	0.84
Pangolin gain	Uncertain	0.25	Position offset: -12
Pangolin loss	Pathogenic	0.84	Position offset: 1
SpliceAI score (max)	Pathogenic	0.99	Details are displayed if max score is > 0.2

Showing 8 of 8 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs753580394;

hg19: chr3-180361907;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar