chrX-50086779-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP3BS1_SupportingBS2

The NM_001127898.4(CLCN5):c.1466C>T(p.Pro489Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,208,443 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P489P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000011 ( 0 hom. 4 hem. )

Consequence

CLCN5
NM_001127898.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 7.82

Publications

0 publications found

Variant links:

Genes affected

CLCN5 (HGNC:2023): (chloride voltage-gated channel 5) This gene encodes a member of the ClC family of chloride ion channels and ion transporters. The encoded protein is primarily localized to endosomal membranes and may function to facilitate albumin uptake by the renal proximal tubule. Mutations in this gene have been found in Dent disease and renal tubular disorders complicated by nephrolithiasis. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2013]

CLCN5 Gene-Disease associations (from GenCC):

Dent disease type 1
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

CLCN5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.775

BS1

Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.0000109 (12/1097637) while in subpopulation AFR AF = 0.000265 (7/26389). AF 95% confidence interval is 0.000124. There are 0 homozygotes in GnomAdExome4. There are 4 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Hemizygotes in GnomAdExome4 at 4 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127898.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLCN5	NM_001127898.4	MANE Select	c.1466C>T	p.Pro489Leu	missense	Exon 11 of 15	NP_001121370.1	P51795-2
CLCN5	NM_001440756.1		c.1478C>T	p.Pro493Leu	missense	Exon 11 of 15	NP_001427685.1
CLCN5	NM_001440757.1		c.1478C>T	p.Pro493Leu	missense	Exon 11 of 15	NP_001427686.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLCN5	ENST00000376091.8	TSL:2 MANE Select	c.1466C>T	p.Pro489Leu	missense	Exon 11 of 15	ENSP00000365259.3	P51795-2
CLCN5	ENST00000307367.2	TSL:1	c.1256C>T	p.Pro419Leu	missense	Exon 8 of 12	ENSP00000304257.2	P51795-1
CLCN5	ENST00000376108.7	TSL:1	c.1256C>T	p.Pro419Leu	missense	Exon 8 of 12	ENSP00000365276.3	P51795-1

Frequencies

GnomAD3 genomes

AF:

0.0000271

AC:

AN:

110806

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000986

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000546

AC:

AN:

183163

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1097637

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

363003

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

26389

American (AMR)

AF:

0.00

AC:

AN:

35199

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19374

East Asian (EAS)

AF:

0.00

AC:

AN:

30203

South Asian (SAS)

AF:

0.00

AC:

AN:

54135

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40533

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4129

European-Non Finnish (NFE)

AF:

0.00000594

AC:

AN:

841598

Other (OTH)

AF:

0.00

AC:

AN:

46077

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

GnomAD4 genome

AF:

0.0000271

AC:

AN:

110806

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33034

show subpopulations

African (AFR)

AF:

0.0000986

AC:

AN:

30438

American (AMR)

AF:

0.00

AC:

AN:

10348

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2639

East Asian (EAS)

AF:

0.00

AC:

AN:

3517

South Asian (SAS)

AF:

0.00

AC:

AN:

2593

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5840

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53038

Other (OTH)

AF:

0.00

AC:

AN:

1474

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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.:

Bravo

AF:

0.0000227

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

CLCN5-related disorder (1)

Hypophosphatemic rickets, X-linked recessive (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.78

MetaSVM

Uncertain

0.14

MutationAssessor

Benign

1.7

PhyloP100

7.8

PrimateAI

Uncertain

0.53

PROVEAN

Pathogenic

-4.7

REVEL

Uncertain

0.59

Sift

Uncertain

0.0090

Sift4G

Benign

0.078

Polyphen

0.16

Vest4

0.34

MVP

0.69

MPC

0.63

ClinPred

0.83

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.38

gMVP

0.84

Mutation Taster

=75/25

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over