rs200353947

Positions:

• chr3-180616289-T-TA

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PVS1_Moderate BP6_Very_Strong BS1 BS2

The NM_181426.2(CCDC39):​c.2660_2661insT​(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

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC39	NM_181426.2	c.2660_2661insT	p.Ser888IlefsTer6	frameshift_variant	19/20	ENST00000476379.6
TTC14	NM_001288582.2	c.1775-1090dup		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC39	ENST00000476379.6	c.2660_2661insT	p.Ser888IlefsTer6	frameshift_variant	19/20	2	NM_181426.2	P2

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

GnomAD3 exomes AF: 0.00792 AC: 1970 AN: 248856 Hom.: 15 AF XY: 0.00783 AC XY: 1057 AN XY: 134994

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 SAS exome AF: 0.00147

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

Gnomad4 AFR exome AF: 0.00138

Gnomad4 AMR exome AF: 0.00403

Gnomad4 ASJ exome AF: 0.00751

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00165

Gnomad4 FIN exome AF: 0.0168

Gnomad4 NFE exome AF: 0.0119

Gnomad4 OTH exome AF: 0.00853

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

Gnomad4 AFR AF: 0.00224

Gnomad4 AMR AF: 0.00700

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.0156

Gnomad4 NFE AF: 0.0121

Gnomad4 OTH AF: 0.0147

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

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 12, 2015	- -

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 14, 2017	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 02, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	CCDC39: BS1, BS2; TTC14: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs200353947; hg19: chr3-180334077;