rs746361802

Variant names:

• chr21-32603260-C-CGCCTCTGCCT
• rs746361802
• NM_021254.4:c.557_566dupAGGCAGAGGC

Variant summary

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

The NM_021254.4(CFAP298):​c.557_566dupAGGCAGAGGC​(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 (★★). Synonymous variant affecting the same amino acid position (i.e. A189A) has been classified as Likely benign. 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.27

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-TCP10L (HGNC:54636): (CFAP298-TCP10L readthrough) This locus represents naturally occurring readthrough transcription between the neighboring chromosome 21 open reading frame 59 (C21orf59) and TCP10L (t-complex 10 like) genes on chromosome 21. Readthrough transcripts may encode a fusion protein that shares sequence identity with each individual gene product. [provided by RefSeq, Apr 2017]

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 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 rank	MANE	Protein	UniProt
CFAP298	NM_021254.4	c.557_566dupAGGCAGAGGC	p.Gln190GlyfsTer26	frameshift_variant	Exon 5 of 7	ENST00000290155.8	NP_067077.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFAP298	ENST00000290155.8	c.557_566dupAGGCAGAGGC	p.Gln190GlyfsTer26	frameshift_variant	Exon 5 of 7	1	NM_021254.4	ENSP00000290155.3
CFAP298-TCP10L	ENST00000673807.1	c.557_566dupAGGCAGAGGC	p.Gln190GlyfsTer26	frameshift_variant	Exon 5 of 8			ENSP00000501088.1

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152224 Hom.: 0 Cov.: 32

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: 46 AN: 251418 Hom.: 0 AF XY: 0.000206 AC XY: 28 AN XY: 135886

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.: 0 Cov.: 32 AF XY: 0.000219 AC XY: 159 AN XY: 727218

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: 32 AN: 152342 Hom.: 0 Cov.: 32 AF XY: 0.000268 AC XY: 20 AN XY: 74494

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.: 0

Bravo AF: 0.000144

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia 26 Pathogenic:3

-

Biology Pathology Center, Lille University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 08, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with primary ciliary dyskinesia 26 (MIM#615500) (PMIDs: 24094744, 26904945). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (53 heterozygotes, 0 homozygotes). (SP) 0703 - Other NMD predicted variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. Three comparable NMD predicted variants have been reported as pathogenic in ClinVar and the literature (PMID:24094744). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been reported three times in ClinVar as pathogenic. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Jul 02, 2021

Johns Hopkins Genomics, Johns Hopkins University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs746361802; hg19: chr21-33975570;