rs863223325

chr12-48918750-GTA-Gchr12-48918750-GTA-GTATA

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_033124.5(CCDC65):c.877_878del(p.Ile293ProfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000132 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: CCDC65 NM_033124.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 0.239

Genes affected

CCDC65 (HGNC:29937): (coiled-coil domain containing 65) This gene encodes a sperm tail protein that is highly expressed in adult testis, spermatocytes and spermatids. The protein plays a critical role in the assembly of the nexin-dynein regulatory complex. Mutations in this gene result in primary ciliary dyskinesia. [provided by RefSeq, Nov 2013]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-48918750-GTA-G is Pathogenic according to our data. Variant chr12-48918750-GTA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 88685.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC65	NM_033124.5	c.877_878del	p.Ile293ProfsTer2	frameshift_variant	6/8	ENST00000320516.5
CCDC65	NM_001286957.2	c.448_449del	p.Ile150ProfsTer2	frameshift_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC65	ENST00000320516.5	c.877_878del	p.Ile293ProfsTer2	frameshift_variant	6/8	1	NM_033124.5	P2

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000203 AC: 51 AN: 251484 Hom.: 0 AF XY: 0.000199 AC XY: 27 AN XY: 135922

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00427

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000703

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000130 AC: 190 AN: 1461862 Hom.: 0 AF XY: 0.000135 AC XY: 98 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00432

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000486

Gnomad4 OTH exome AF: 0.000381

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74328

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000136 Hom.: 0

Bravo AF: 0.000151

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia 27 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Dec 17, 2021	CCDC65 c.877_878del has been reported in the homozygous state in multiple individuals with primary ciliary dyskinesia. This variant (rs1272967209) has an entry in ClinVar and has been identified in a large population dataset. The minor allele frequency is neither low enough to consider the variant rare (<0.1%) nor high enough to consider it a population polymorphism (>1%) within the Ashkenazi Jewish subpopulation (gnomAD: 45/10370 alleles; 0.4339%, no homozygotes). This frameshift variant results in a premature stop codon in exon 6 of 8 likely leading to nonsense-mediated decay and lack of protein production. We consider CCDC65 c.877_878del to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change creates a premature translational stop signal (p.Ile293Profs*2) in the CCDC65 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CCDC65 are known to be pathogenic (PMID: 23991085, 24094744). This variant is present in population databases (rs748630203, gnomAD 0.4%). This premature translational stop signal has been observed in individual(s) with primary ciliary dyskinesia (PMID: 23991085, 24094744). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 23991085, 24094744). This variant is also known as 876_877delAT. ClinVar contains an entry for this variant (Variation ID: 88685). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 03, 2013	- -

Primary ciliary dyskinesia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 30, 2015

The p.Ile293fs variant in CCDC65 has been previously reported in 3 Ashkenazi Jew ish individuals with primary ciliary dyskinesia (PCD) and segregated with diseas e in 1 affected family member (Austin-Tse 2013, Horani 2013). All of these indiv iduals were homozygous for the variant. This variant has also been identified in 20/66728 European chromosomes by the Exome Aggregation Consortium (ExAC, http:/ /exac.broadinstitute.org) and in 0.14% (3/2070) of chromosomes from an Ashkenazi Jewish control cohort (Fedick 2015). Although this variant has been seen in the general population, its frequency is still low enough to be consistent with a r ecessive carrier frequency. The p.Ile293fs variant is predicted to cause a frame shift, which alters the protein?s amino acid sequence beginning at position 293 and leads to a premature termination codon 2 amino acids downstream. This altera tion is then predicted to lead to a truncated or absent protein. In vitro studie s have demonstrated that the CCDC65 protein was absent in cells derived from an individual homozygous for this variant (Horani 2013). Functional studies in huma n cell lines and the zebrafish model provided some evidence that loss of functio n of the CCDC65 gene may cause cilia motility defects (Horani 2013, Austin-Tse 2 013), though these types of assays may not accurately reflect biological functio n. The p.Ile293fs variant is currently the only variant in CCDC65 gene that has been reported in individuals with PCD, therefore additional studies are needed t o fully understand the role of the CCDC65 gene in disease. In summary, although additional studies are required to fully establish its clinical significance, th e p.Ile293fs variant is likely pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 30, 2023

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; This variant is associated with the following publications: (PMID: 24094744, 23991085, 34693619) -

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: rs863223325; hg19: chr12-49312533;