dbSNP rs766485323: CLXN:p.Arg98Leu (chr8-48730566-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_024593.4(CLXN):c.293G>T(p.Arg98Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,458,090 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R98Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CLXN
NM_024593.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.08

Variant links:

Genes affected

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

CLXN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLXN	NM_024593.4 link	c.293G>T	p.Arg98Leu	missense_variant	Exon 3 of 6	ENST00000262103.8	NP_078869.1	Q9HAE3-1A0A024R7U5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLXN	ENST00000262103.8 link	c.293G>T	p.Arg98Leu	missense_variant	Exon 3 of 6	1	NM_024593.4	ENSP00000262103.3		Q9HAE3-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248674

Hom.:

AF XY:

0.00000743

AC XY:

AN XY:

134520

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000466

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458090

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725432

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

.;T;.

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.98

D;D;.

M_CAP

Uncertain

0.10

MetaRNN

Pathogenic

0.88

D;D;D

MetaSVM

Uncertain

0.29

MutationAssessor

Uncertain

2.3

.;M;.

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-6.5

D;D;D

REVEL

Uncertain

0.57

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.010

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.95

MutPred

0.47

.;Loss of phosphorylation at S100 (P = 0.0616);.;

MVP

0.94

MPC

0.24

ClinPred

1.0

GERP RS

4.4

Varity_R

0.68

gMVP

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.57

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.32

Position offset: -3

DS_DL_spliceai

0.57

Position offset: -26

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over