chr8-48729824-C-A

Variant names:

• chr8-48729824-C-A
• rs1803178017
• NM_024593.4:c.367G>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.367G>T​(p.Glu123*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLXN NM_024593.4 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.97
• Publications: 0 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 8-48729824-C-A is Pathogenic according to our data. Variant chr8-48729824-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2664149.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.367G>T	p.Glu123*	stop_gained	Exon 4 of 6	NP_078869.1	Q9HAE3-1
	CLXN	NM_001142857.2		c.211G>T	p.Glu71*	stop_gained	Exon 3 of 6	NP_001136329.1	Q9HAE3-2
	CLXN	NM_001363973.3		c.211G>T	p.Glu71*	stop_gained	Exon 3 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.367G>T	p.Glu123*	stop_gained	Exon 4 of 6	ENSP00000262103.3	Q9HAE3-1
	CLXN	ENST00000521701.5	TSL:1	n.164G>T		splice_region non_coding_transcript_exon	Exon 3 of 6	ENSP00000430374.1	H9KVD9
	CLXN	ENST00000521002.5	TSL:1	n.292-712G>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		6.0
Vest4		0.51
ClinPred		1.0	D
GERP RS		5.5
PromoterAI		-0.039	Neutral
Mutation Taster		=27/173	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.68		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.68		Position offset: -3

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

Other links and lift over

dbSNP: rs1803178017; hg19: chr8-49642383; COSMIC: COSV50619974; COSMIC: COSV50619974;