rs746361802

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 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
• Publications: 0 publications found

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

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 21-32603260-C-CGCCTCTGCCT is Pathogenic according to our data. Variant chr21-32603260-C-CGCCTCTGCCT is described in ClinVar as Pathogenic. ClinVar VariationId is 525239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021254.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFAP298	NM_021254.4	MANE Select	c.557_566dupAGGCAGAGGC	p.Gln190GlyfsTer26	frameshift	Exon 5 of 7	NP_067077.1	P57076
	CFAP298-TCP10L	NM_001350338.2		c.557_566dupAGGCAGAGGC	p.Gln190GlyfsTer26	frameshift	Exon 5 of 8	NP_001337267.1	A0A669KAY3
	CFAP298	NM_001350337.2		c.557_566dupAGGCAGAGGC	p.Gln190GlyfsTer26	frameshift	Exon 5 of 6	NP_001337266.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFAP298	ENST00000290155.8	TSL:1 MANE Select	c.557_566dupAGGCAGAGGC	p.Gln190GlyfsTer26	frameshift	Exon 5 of 7	ENSP00000290155.3	P57076
	CFAP298-TCP10L	ENST00000673807.1		c.557_566dupAGGCAGAGGC	p.Gln190GlyfsTer26	frameshift	Exon 5 of 8	ENSP00000501088.1	A0A669KAY3
	CFAP298	ENST00000382549.8	TSL:1	c.557_566dupAGGCAGAGGC	p.Gln190GlyfsTer26	frameshift	Exon 5 of 5	ENSP00000371989.4	D3DSE6

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

GnomAD2 exomes AF: 0.000183 AC: 46 AN: 251418 AF XY: 0.000206

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 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

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000267 AC: 23 AN: 86256

European-Finnish (FIN) AF: 0.000805 AC: 43 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000223 AC: 248 AN: 1111974

Other (OTH) AF: 0.0000828 AC: 5 AN: 60392

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152342 Hom.: 0 Cov.: 32 AF XY: 0.000268 AC XY: 20 AN XY: 74494

African (AFR) AF: 0.0000722 AC: 3 AN: 41570

American (AMR) AF: 0.00 AC: 0 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4830

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000432 Hom.: 0

Bravo AF: 0.000144

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Primary ciliary dyskinesia 26 (3)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.3
Mutation Taster		=8/192	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs746361802; hg19: chr21-33975570;