Genetic Variant NM_001127898.4:c.215A>C (chrX-50069930-A-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_001127898.4(CLCN5):c.215A>C(p.Asp72Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000058 in 1,207,668 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 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 0.0000090 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.0000055 ( 0 hom. 2 hem. )

Consequence

CLCN5
NM_001127898.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.22

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 -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.871

BS2

High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN5	NM_001127898.4 link	c.215A>C	p.Asp72Ala	missense_variant	Exon 5 of 15	ENST00000376091.8	NP_001121370.1	P51795-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCN5	ENST00000376091.8 link	c.215A>C	p.Asp72Ala	missense_variant	Exon 5 of 15	2	NM_001127898.4	ENSP00000365259.3		P51795-2

Frequencies

GnomAD3 genomes

AF:

0.00000895

AC:

AN:

111718

Hom.:

Cov.:

AF XY:

0.0000295

AC XY:

AN XY:

33926

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000664

GnomAD3 exomes

AF:

0.00000549

AC:

AN:

182198

Hom.:

AF XY:

0.00

AC XY:

AN XY:

66844

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000367

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1095950

Hom.:

Cov.:

AF XY:

0.00000553

AC XY:

AN XY:

361564

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000285

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:

0.00000595

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000895

AC:

AN:

111718

Hom.:

Cov.:

AF XY:

0.0000295

AC XY:

AN XY:

33926

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.000664

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jul 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 2 of the CLCN5 protein (p.Asp2Ala). This variant is present in population databases (no rsID available, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with CLCN5-related conditions. 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 disruptive. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.50

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.48

.;.;T;T;T

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

.;D;.;.;D

M_CAP

Pathogenic

0.92

MetaRNN

Pathogenic

0.87

D;D;D;D;D

MetaSVM

Uncertain

0.70

MutationAssessor

Uncertain

2.1

.;.;M;M;M

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-2.4

N;N;D;.;D

REVEL

Pathogenic

0.82

Sift

Benign

0.069

T;T;D;.;D

Sift4G

Uncertain

0.010

D;D;D;.;D

Polyphen

0.70

P;P;D;D;D

Vest4

0.75

MutPred

0.40

.;.;Gain of catalytic residue at D2 (P = 0.1244);Gain of catalytic residue at D2 (P = 0.1244);Gain of catalytic residue at D2 (P = 0.1244);

MVP

0.99

MPC

0.89

ClinPred

0.58

GERP RS

5.5

Varity_R

0.50

gMVP

0.87

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