rs746361802

Variant summary

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

The NM_021254.4(CFAP298):c.566_567insAGGCAGAGGC(p.Gln190GlyfsTer26) variant causes a frameshift change. The variant allele was found at a frequency of 0.000221 in 1,614,162 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

CFAP298
NM_021254.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 6.27

Variant links:

Genes affected

CFAP298 (HGNC:1301): (cilia and flagella associated protein 298) This gene encodes a protein that plays a critical role in dynein arm assembly and motile cilia function. Mutations in this gene result in primary ciliary dyskinesia. Naturally occuring readthrough transcription occurs from this locus to the downstream t-complex 10 like (TCP10L) gene. [provided by RefSeq, Apr 2017]

CFAP298 links:

CFAP298-TCP10L (HGNC:):

CFAP298-TCP10L links:

Genome browser will be placed here

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 21-32603260-C-CGCCTCTGCCT is Pathogenic according to our data. Variant chr21-32603260-C-CGCCTCTGCCT is described in ClinVar as [Pathogenic]. Clinvar id is 525239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFAP298	NM_021254.4 linkuse as main transcript	c.566_567insAGGCAGAGGC	p.Gln190GlyfsTer26	frameshift_variant	5/7	ENST00000290155.8
CFAP298-TCP10L	NR_146638.2 linkuse as main transcript	n.700_701insAGGCAGAGGC		non_coding_transcript_exon_variant	5/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFAP298	ENST00000290155.8 linkuse as main transcript	c.566_567insAGGCAGAGGC	p.Gln190GlyfsTer26	frameshift_variant	5/7	1	NM_021254.4	P1

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000183

AC:

AN:

251418

Hom.:

AF XY:

0.000206

AC XY:

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.000554

Gnomad NFE exome

AF:

0.000229

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000222

AC:

324

AN:

1461820

Hom.:

Cov.:

AF XY:

0.000219

AC XY:

159

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000267

Gnomad4 FIN exome

AF:

0.000805

Gnomad4 NFE exome

AF:

0.000223

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.000210

AC:

AN:

152342

Hom.:

Cov.:

AF XY:

0.000268

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.000279

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000432

Hom.:

Bravo

AF:

0.000144

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 26

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Biology Pathology Center, Lille University Hospital	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Jul 02, 2021	CFAP298 c.557_566dup (rs746361802) is rare (<0.1%) in a large population dataset (gnomAD: 53/282824 total alleles; 0.019%; no homozygotes) and has been reported in ClinVar (Variation ID: 525239). It has not been reported in the literature, to our knowledge. This frameshift variant results in a premature stop codon in exon 5 of 7 likely leading to nonsense-mediated decay and lack of protein production. We consider CFAP298 c.557_566dup to be pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

This sequence change creates a premature translational stop signal (p.Gln190Glyfs*26) in the CFAP298 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CFAP298 are known to be pathogenic (PMID: 24094744). This variant is present in population databases (rs746361802, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with CFAP298-related conditions. ClinVar contains an entry for this variant (Variation ID: 525239). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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