X-50042394-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001127898.4(CLCN5):c.95A>G(p.Asp32Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000259 in 1,161,946 control chromosomes in the GnomAD database, including 1 homozygotes. There are 99 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00034 ( 1 hom., 9 hem., cov: 22)

Exomes 𝑓: 0.00025 ( 0 hom. 90 hem. )

Consequence

CLCN5
NM_001127898.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 7.03

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 Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008176386).

BP6

Variant X-50042394-A-G is Benign according to our data. Variant chrX-50042394-A-G is described in ClinVar as [Benign]. Clinvar id is 3048658.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00034 (38/111825) while in subpopulation NFE AF= 0.00015 (8/53163). AF 95% confidence interval is 0.0000745. There are 1 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCN5	NM_001127898.4 linkuse as main transcript	c.95A>G	p.Asp32Gly	missense_variant	4/15	ENST00000376091.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCN5	ENST00000376091.8 linkuse as main transcript	c.95A>G	p.Asp32Gly	missense_variant	4/15	2	NM_001127898.4	P3	P51795-2
CLCN5	ENST00000376088.7 linkuse as main transcript	c.95A>G	p.Asp32Gly	missense_variant	4/15	2		P3	P51795-2
CLCN5	ENST00000482218.2 linkuse as main transcript	c.95A>G	p.Asp32Gly	missense_variant	3/3	3
CLCN5	ENST00000643129.1 linkuse as main transcript	c.59A>G	p.Asp20Gly	missense_variant, NMD_transcript_variant	1/14

Frequencies

GnomAD3 genomes

AF:

0.000340

AC:

AN:

111825

Hom.:

Cov.:

AF XY:

0.000265

AC XY:

AN XY:

34007

show subpopulations

Gnomad AFR

AF:

0.0000326

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.0110

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000150

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000563

AC:

AN:

120844

Hom.:

AF XY:

0.000635

AC XY:

AN XY:

34666

show subpopulations

Gnomad AFR exome

AF:

0.000128

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00928

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000609

Gnomad OTH exome

AF:

0.00154

GnomAD4 exome

AF:

0.000250

AC:

263

AN:

1050121

Hom.:

Cov.:

AF XY:

0.000270

AC XY:

AN XY:

333839

show subpopulations

Gnomad4 AFR exome

AF:

0.0000790

Gnomad4 AMR exome

AF:

0.0000343

Gnomad4 ASJ exome

AF:

0.0108

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000356

Gnomad4 OTH exome

AF:

0.000702

GnomAD4 genome

AF:

0.000340

AC:

AN:

111825

Hom.:

Cov.:

AF XY:

0.000265

AC XY:

AN XY:

34007

show subpopulations

Gnomad4 AFR

AF:

0.0000326

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.0110

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000150

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000583

Hom.:

Bravo

AF:

0.000374

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000728

AC:

ExAC

AF:

0.000409

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

CLCN5-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 11, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.31

Cadd

Uncertain

Dann

Uncertain

0.99

FATHMM_MKL

Uncertain

0.94

M_CAP

Pathogenic

0.69

MetaRNN

Benign

0.0082

T;T;T

MetaSVM

Uncertain

0.046

MutationTaster

Benign

0.90

D;D

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.8

N;N;.

REVEL

Uncertain

0.38

Sift

Uncertain

0.0020

D;D;.

Sift4G

Benign

0.092

T;T;T

Polyphen

0.45

B;B;.

Vest4

0.27

MVP

0.80

MPC

1.2

ClinPred

0.087

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.39

Splicing

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