3-180652189-C-T

Variant names:

• chr3-180652189-C-T
• rs79329972
• NM_181426.2:c.1008G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_181426.2(CCDC39):​c.1008G>A​(p.Lys336Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 1,528,792 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (50 hom.)
• Consequence: CCDC39 NM_181426.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.37
• 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: ClinGen, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000145075 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 3-180652189-C-T is Benign according to our data. Variant chr3-180652189-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.37 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00272 (414/152114) while in subpopulation EAS AF = 0.0394 (204/5182). AF 95% confidence interval is 0.0349. There are 4 homozygotes in GnomAd4. There are 252 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.1008G>A	p.Lys336Lys	synonymous	Exon 8 of 20	NP_852091.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC39	ENST00000476379.6	TSL:2 MANE Select	c.1008G>A	p.Lys336Lys	synonymous	Exon 8 of 20	ENSP00000417960.2
	CCDC39	ENST00000936067.1		c.915G>A	p.Lys305Lys	synonymous	Exon 7 of 19	ENSP00000606126.1
	CCDC39	ENST00000651046.1		c.816G>A	p.Lys272Lys	synonymous	Exon 7 of 19	ENSP00000499175.1

Frequencies

GnomAD3 genomes AF: 0.00273 AC: 415 AN: 151996 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.0393

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0110

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000971

Gnomad OTH AF: 0.000959

GnomAD2 exomes AF: 0.00419 AC: 612 AN: 146088 AF XY: 0.00387

Gnomad AFR exome AF: 0.000259

Gnomad AMR exome AF: 0.000137

Gnomad ASJ exome AF: 0.00120

Gnomad EAS exome AF: 0.0367

Gnomad FIN exome AF: 0.0110

Gnomad NFE exome AF: 0.000687

Gnomad OTH exome AF: 0.00193

GnomAD4 exome AF: 0.00200 AC: 2759 AN: 1376678 Hom.: 50 Cov.: 28 AF XY: 0.00198 AC XY: 1344 AN XY: 678014

African (AFR) AF: 0.0000327 AC: 1 AN: 30582

American (AMR) AF: 0.000272 AC: 9 AN: 33042

Ashkenazi Jewish (ASJ) AF: 0.00125 AC: 31 AN: 24892

East Asian (EAS) AF: 0.0440 AC: 1533 AN: 34818

South Asian (SAS) AF: 0.000839 AC: 61 AN: 72704

European-Finnish (FIN) AF: 0.00910 AC: 446 AN: 48990

Middle Eastern (MID) AF: 0.00112 AC: 6 AN: 5360

European-Non Finnish (NFE) AF: 0.000512 AC: 547 AN: 1069144

Other (OTH) AF: 0.00219 AC: 125 AN: 57146

GnomAD4 genome AF: 0.00272 AC: 414 AN: 152114 Hom.: 4 Cov.: 32 AF XY: 0.00339 AC XY: 252 AN XY: 74376

African (AFR) AF: 0.000144 AC: 6 AN: 41532

American (AMR) AF: 0.000196 AC: 3 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3470

East Asian (EAS) AF: 0.0394 AC: 204 AN: 5182

South Asian (SAS) AF: 0.00229 AC: 11 AN: 4812

European-Finnish (FIN) AF: 0.0110 AC: 116 AN: 10562

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

European-Non Finnish (NFE) AF: 0.000971 AC: 66 AN: 67964

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.00107 Hom.: 1

Bravo AF: 0.00215

Asia WGS AF: 0.0100 AC: 35 AN: 3470

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	6.5
DANN	Benign	0.67
PhyloP100		1.4
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs79329972; hg19: chr3-180369977;