rs879255583

Positions:

• chrX-10213768-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001830.4(CLCN4):​c.1664C>T​(p.Ala555Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A555A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 24)
• Consequence: CLCN4 NM_001830.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 U:1
• Conservation: PhyloP100: 5.99

Genes affected

CLCN4 (HGNC:2022): (chloride voltage-gated channel 4) The CLCN family of voltage-dependent chloride channel genes comprises nine members (CLCN1-7, Ka and Kb) which demonstrate quite diverse functional characteristics while sharing significant sequence homology. Chloride channel 4 has an evolutionary conserved CpG island and is conserved in both mouse and hamster. This gene is mapped in close proximity to APXL (Apical protein Xenopus laevis-like) and OA1 (Ocular albinism type I), which are both located on the human X chromosome at band p22.3. The physiological role of chloride channel 4 remains unknown but may contribute to the pathogenesis of neuronal disorders. Alternate splicing results in two transcript variants that encode different proteins. [provided by RefSeq, Mar 2012]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001830.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CLCN4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969
• PP5: Variant X-10213768-C-T is Pathogenic according to our data. Variant chrX-10213768-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 209115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-10213768-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCN4	NM_001830.4	c.1664C>T	p.Ala555Val	missense_variant	11/13	ENST00000380833.9
CLCN4	NM_001256944.2	c.1382C>T	p.Ala461Val	missense_variant	9/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCN4	ENST00000380833.9	c.1664C>T	p.Ala555Val	missense_variant	11/13	1	NM_001830.4	P4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 08, 2022	Published functional studies demonstrate A555V reduced the outwardly rectifying CIC-4 current, suggesting a damaging effect (Palmer et al,. 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26633542, 34426522, 27550844) -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 15, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 04, 2024	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 555 of the CLCN4 protein (p.Ala555Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with CLCN4-related conditions (PMID: 27550844). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 209115). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CLCN4 protein function. Experimental studies have shown that this missense change affects CLCN4 function (PMID: 27550844). For these reasons, this variant has been classified as Pathogenic. -

CLCN4-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Sydney Children's Hospital, SCHN

Mar 22, 2016

De novo variant. Clinical phenotype consistent with case series of individuals with CLCN4 related disorder. -

Intellectual disability, X-linked 49 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Gene2Care/ Palmer Lab, University of New South Wales

May 27, 2022

- -

Inborn genetic diseases Uncertain:1

Uncertain significance, flagged submission

clinical testing

Ambry Genetics

Jun 06, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Benign	23
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	0.83	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.3	D;D;D
REVEL	Pathogenic	0.73
Sift	Benign	0.079	T;D;D
Sift4G	Benign	0.13	T;T;T
Polyphen		0.96	.;D;.
Vest4		0.73
MutPred		0.78		.;Gain of sheet (P = 0.0827);.;
MVP		0.93
MPC		2.1
ClinPred		0.95	D
GERP RS		5.5
Varity_R		0.54
gMVP		0.97

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

Other links and lift over

dbSNP: rs879255583; hg19: chrX-10181808; COSMIC: COSV66465220;