Genetic Variant CLXN:p.Glu123Lys (chr8-48729824-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_024593.4(CLXN):c.367G>A(p.Glu123Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,613,154 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CLXN
NM_024593.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.97

Publications

0 publications found

Variant links:

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

CLXN links:

ENSG00000253608 (HGNC:):

ENSG00000253608 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLXN	NM_024593.4	MANE Select	c.367G>A	p.Glu123Lys	missense	Exon 4 of 6	NP_078869.1	Q9HAE3-1
CLXN	NM_001142857.2		c.211G>A	p.Glu71Lys	missense	Exon 3 of 6	NP_001136329.1	Q9HAE3-2
CLXN	NM_001363973.3		c.211G>A	p.Glu71Lys	missense	Exon 3 of 6	NP_001350902.1	Q9HAE3-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLXN	ENST00000262103.8	TSL:1 MANE Select	c.367G>A	p.Glu123Lys	missense	Exon 4 of 6	ENSP00000262103.3	Q9HAE3-1
CLXN	ENST00000521701.5	TSL:1	n.164G>A		splice_region non_coding_transcript_exon	Exon 3 of 6	ENSP00000430374.1	H9KVD9
CLXN	ENST00000521002.5	TSL:1	n.292-712G>A		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460958

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726756

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26090

East Asian (EAS)

AF:

0.00

AC:

AN:

39658

South Asian (SAS)

AF:

0.00

AC:

AN:

86162

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53340

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111410

Other (OTH)

AF:

0.00

AC:

AN:

60354

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41448

American (AMR)

AF:

0.0000654

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.37

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.99

M_CAP

Benign

0.063

MetaRNN

Uncertain

0.64

MetaSVM

Benign

-0.29

MutationAssessor

Uncertain

2.3

PhyloP100

6.0

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-3.8

REVEL

Uncertain

0.57

Sift

Uncertain

0.0040

Sift4G

Benign

0.071

Polyphen

1.0

Vest4

0.45

MutPred

0.52

Gain of methylation at E123 (P = 0.0103)

MVP

0.83

MPC

0.29

ClinPred

0.99

GERP RS

5.5

PromoterAI

0.00030

Neutral

(source)

Varity_R

0.65

gMVP

0.62

Mutation Taster

=48/52

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over