X-50086779-C-T

Position:

chrX-50086779-C-T

Variant summary

Our verdict is Likely benign. Variant got -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 (★★).

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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.775

BS1

Variant frequency is greater than expected in population afr. gnomad4_exome 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 gnomad4_exome. There are 4 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Hemizygotes in GnomAdExome4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCN5	NM_001127898.4 linkuse as main transcript	c.1466C>T	p.Pro489Leu	missense_variant	11/15	ENST00000376091.8	NP_001121370.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCN5	ENST00000376091.8 linkuse as main transcript	c.1466C>T	p.Pro489Leu	missense_variant	11/15	2	NM_001127898.4	ENSP00000365259	P3	P51795-2

Frequencies

GnomAD3 genomes

AF:

0.0000271

AC:

AN:

110806

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33034

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

GnomAD3 exomes

AF:

0.00000546

AC:

AN:

183163

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67689

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:

0.00

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

Gnomad4 AFR exome

AF:

0.000265

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:

0.00

Gnomad4 NFE exome

AF:

0.00000594

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000271

AC:

AN:

110806

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33034

show subpopulations

Gnomad4 AFR

AF:

0.0000986

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

CLCN5-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 05, 2024

The CLCN5 c.1256C>T variant is predicted to result in the amino acid substitution p.Pro419Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0012% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 25, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬† is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 585284). This variant has not been reported in the literature in individuals affected with CLCN5-related conditions. This variant is present in population databases (rs782602018, gnomAD 0.001%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 419 of the CLCN5 protein (p.Pro419Leu). -

Hypophosphatemic rickets, X-linked recessive

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center of Genomic medicine, Geneva, University Hospital of Geneva

May 16, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

.;.;D;D;D;.

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

.;D;.;.;D;D

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.78

D;D;D;D;D;D

MetaSVM

Uncertain

0.14

MutationAssessor

Benign

1.7

.;.;L;L;L;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.53

PROVEAN

Pathogenic

-4.7

D;D;D;.;D;.

REVEL

Uncertain

0.59

Sift

Uncertain

0.0090

D;D;D;.;D;.

Sift4G

Benign

0.078

T;T;T;.;T;.

Polyphen

0.16

B;B;B;B;B;.

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

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

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over