rs200353947

Variant names:

• chr3-180616289-T-TA
• rs200353947
• NM_181426.2:c.2660dupT

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PVS1_Moderate BP6_Very_Strong BS1 BS2

The NM_181426.2(CCDC39):​c.2660dupT​(p.Ser888IlefsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 1,613,166 control chromosomes in the GnomAD database, including 108 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0083 (9 hom., cov: 32)
  • Exomes 𝑓: 0.010 (99 hom.)
• Consequence: CCDC39 NM_181426.2 frameshift
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.53
• Publications: 8 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]

TTC14 (HGNC:24697): (tetratricopeptide repeat domain 14) Predicted to enable nucleic acid binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000145075 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0587 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• BP6: Variant 3-180616289-T-TA is Benign according to our data. Variant chr3-180616289-T-TA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 194994.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00827 (1259/152278) while in subpopulation NFE AF = 0.0121 (824/68020). AF 95% confidence interval is 0.0114. There are 9 homozygotes in GnomAd4. There are 587 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 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.2660dupT	p.Ser888IlefsTer6	frameshift	Exon 19 of 20	NP_852091.1	Q9UFE4-1
	TTC14	NM_001288582.2		c.1775-1090dupA		intron	N/A	NP_001275511.1	Q96N46-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC39	ENST00000476379.6	TSL:2 MANE Select	c.2660dupT	p.Ser888IlefsTer6	frameshift	Exon 19 of 20	ENSP00000417960.2	Q9UFE4-1
	TTC14	ENST00000382584.8	TSL:1	c.1775-1090dupA		intron	N/A	ENSP00000372027.4	Q96N46-2
	CCDC39	ENST00000936067.1		c.2567dupT	p.Ser857IlefsTer6	frameshift	Exon 18 of 19	ENSP00000606126.1

Frequencies

GnomAD3 genomes AF: 0.00827 AC: 1259 AN: 152160 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00224

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00701

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0156

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0121

Gnomad OTH AF: 0.0148

GnomAD2 exomes AF: 0.00792 AC: 1970 AN: 248856 AF XY: 0.00783

Gnomad AFR exome AF: 0.00207

Gnomad AMR exome AF: 0.00349

Gnomad ASJ exome AF: 0.00736

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0165

Gnomad NFE exome AF: 0.0114

Gnomad OTH exome AF: 0.00960

GnomAD4 exome AF: 0.0104 AC: 15207 AN: 1460888 Hom.: 99 Cov.: 31 AF XY: 0.0103 AC XY: 7464 AN XY: 726708

African (AFR) AF: 0.00138 AC: 46 AN: 33438

American (AMR) AF: 0.00403 AC: 180 AN: 44616

Ashkenazi Jewish (ASJ) AF: 0.00751 AC: 196 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00165 AC: 142 AN: 86244

European-Finnish (FIN) AF: 0.0168 AC: 896 AN: 53386

Middle Eastern (MID) AF: 0.00573 AC: 33 AN: 5756

European-Non Finnish (NFE) AF: 0.0119 AC: 13199 AN: 1111306

Other (OTH) AF: 0.00853 AC: 515 AN: 60344

GnomAD4 genome AF: 0.00827 AC: 1259 AN: 152278 Hom.: 9 Cov.: 32 AF XY: 0.00788 AC XY: 587 AN XY: 74458

African (AFR) AF: 0.00224 AC: 93 AN: 41550

American (AMR) AF: 0.00700 AC: 107 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00749 AC: 26 AN: 3470

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

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4826

European-Finnish (FIN) AF: 0.0156 AC: 166 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0121 AC: 824 AN: 68020

Other (OTH) AF: 0.0147 AC: 31 AN: 2116

Alfa AF: 0.0105 Hom.: 7

Bravo AF: 0.00757

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0109

EpiControl AF: 0.0108

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5
Mutation Taster		=128/72	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: rs200353947; hg19: chr3-180334077; COSMIC: COSV106086474;