rs751867551

Variant names:

• chr8-48730567-G-A
• rs751867551
• NM_024593.4:c.292C>T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PVS1 PM2 PP3 PP5_Moderate

The NM_024593.4(CLXN):​c.292C>T​(p.Arg98*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000621 in 1,610,312 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 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: CLXN NM_024593.4 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.97
• Publications: 4 publications found

Genes affected

CLXN (HGNC:25678): (calaxin) Predicted to enable calcium ion binding activity. [provided by Alliance of Genome Resources, Apr 2022]

CLXN Gene-Disease associations (from GenCC):

• ciliary dyskinesia, primary, 53

  Inheritance: AR Classification: STRONG Submitted by: ClinGen

ENSG00000253608 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 13 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
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 8-48730567-G-A is Pathogenic according to our data. Variant chr8-48730567-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2664148.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024593.4. 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
	CLXN	NM_024593.4	MANE Select	c.292C>T	p.Arg98*	stop_gained	Exon 3 of 6	NP_078869.1	Q9HAE3-1
	CLXN	NM_001142857.2		c.136C>T	p.Arg46*	stop_gained	Exon 2 of 6	NP_001136329.1	Q9HAE3-2
	CLXN	NM_001363973.3		c.136C>T	p.Arg46*	stop_gained	Exon 2 of 6	NP_001350902.1	Q9HAE3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLXN	ENST00000262103.8	TSL:1 MANE Select	c.292C>T	p.Arg98*	stop_gained	Exon 3 of 6	ENSP00000262103.3	Q9HAE3-1
	CLXN	ENST00000521701.5	TSL:1	n.136C>T		non_coding_transcript_exon	Exon 2 of 6	ENSP00000430374.1	H9KVD9
	CLXN	ENST00000521002.5	TSL:1	n.292-1455C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152072 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000804 AC: 2 AN: 248660 AF XY: 0.00000744

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000617 AC: 9 AN: 1458240 Hom.: 0 Cov.: 29 AF XY: 0.00000689 AC XY: 5 AN XY: 725500

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33312

American (AMR) AF: 0.00 AC: 0 AN: 44216

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26066

East Asian (EAS) AF: 0.00 AC: 0 AN: 39416

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53126

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000721 AC: 8 AN: 1110312

Other (OTH) AF: 0.00 AC: 0 AN: 60226

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000544044), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152072 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74276

African (AFR) AF: 0.00 AC: 0 AN: 41424

American (AMR) AF: 0.00 AC: 0 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Ciliary dyskinesia, primary, 53 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Uncertain	0.95	D
PhyloP100		7.0
Vest4		0.39
ClinPred		1.0	D
GERP RS		4.4
PromoterAI		-0.015	Neutral
Mutation Taster		=31/169	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.52		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.52		Position offset: -27

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

Other links and lift over

dbSNP: rs751867551; hg19: chr8-49643126;