8-48731371-G-A

Variant names:

• chr8-48731371-G-A
• rs915549726
• NM_024593.4:c.191C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_024593.4(CLXN):​c.191C>T​(p.Thr64Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T64R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLXN NM_024593.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.09
• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.814

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.191C>T	p.Thr64Ile	missense	Exon 2 of 6	NP_078869.1	Q9HAE3-1
	CLXN	NM_001142857.2		c.59-727C>T		intron	N/A	NP_001136329.1	Q9HAE3-2
	CLXN	NM_001363973.3		c.59-727C>T		intron	N/A	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.191C>T	p.Thr64Ile	missense	Exon 2 of 6	ENSP00000262103.3	Q9HAE3-1
	CLXN	ENST00000521002.5	TSL:1	n.292-2259C>T		intron	N/A
	CLXN	ENST00000521701.5	TSL:1	n.59-727C>T		intron	N/A	ENSP00000430374.1	H9KVD9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 249730 AF XY: 0.00000740

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: 0.00

Gnomad OTH exome AF: 0.000165

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.17	T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.061	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		7.1
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.010	D
Polyphen		0.99	D
Vest4		0.76
MutPred		0.48		Loss of relative solvent accessibility (P = 0.114)
MVP		0.92
MPC		0.31
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.75
gMVP		0.62
Mutation Taster		=48/52	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs915549726; hg19: chr8-49643930;