Variant rs863223325 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_033124.5(CCDC65):c.877_878delAT(p.Ile293fs) 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

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 0.239

Variant links:

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]

CCDC65 links:

ENSG00000272822 (HGNC:):

ENSG00000272822 links:

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ACMG classification

Classification made for transcript

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	Protein	UniProt
CCDC65	NM_033124.5 linkuse as main transcript	c.877_878delAT	p.Ile293fs	frameshift_variant	6/8	ENST00000320516.5	NP_149115.2	Q8IXS2-1
CCDC65	NM_001286957.2 linkuse as main transcript	c.448_449delAT	p.Ile150fs	frameshift_variant	6/8		NP_001273886.1	B4DXQ7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC65	ENST00000320516.5 linkuse as main transcript	c.877_878delAT	p.Ile293fs	frameshift_variant	6/8	1	NM_033124.5	ENSP00000312706.4		Q8IXS2-1
ENSG00000272822	ENST00000398092.4 linkuse as main transcript	c.385-14844_385-14843delTA		intron_variant		3		ENSP00000438507.1		F5H423

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

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:

AN:

251484

Hom.:

AF XY:

0.000199

AC XY:

AN XY:

135922

show subpopulations

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.:

AF XY:

0.000135

AC XY:

AN XY:

727230

show subpopulations

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:

AN:

152144

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74328

show subpopulations

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.:

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

LINK: link

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	Labcorp Genetics (formerly Invitae), Labcorp	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

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over