chrX-10220837-C-T

Position:

• chrX-10220837-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The ENST00000380833.9(CLCN4):​c.2152C>T​(p.Arg718Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R718Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: CLCN4 ENST00000380833.9 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 U:1
• Conservation: PhyloP100: 1.89

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 domain CBS 2 (size 58) in uniprot entity CLCN4_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in ENST00000380833.9
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-10220838-G-A is described in Lovd as [Likely_pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CLCN4. . Gene score misZ 4.5166 (greater than the threshold 3.09). GenCC has associacion of gene with non-syndromic X-linked intellectual disability, intellectual disability, X-linked 49.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905
• PP5: Variant X-10220837-C-T is Pathogenic according to our data. Variant chrX-10220837-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 209116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-10220837-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCN4	NM_001830.4	c.2152C>T	p.Arg718Trp	missense_variant	12/13	ENST00000380833.9	NP_001821.2
CLCN4	NM_001256944.2	c.1870C>T	p.Arg624Trp	missense_variant	10/11		NP_001243873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCN4	ENST00000380833.9	c.2152C>T	p.Arg718Trp	missense_variant	12/13	1	NM_001830.4	ENSP00000370213	P4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, X-linked 49 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Gene2Care/ Palmer Lab, University of New South Wales	May 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Aug 10, 2021	PM1, PM2, PP2, PP3, PP5 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 07, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	The variant has been previously reported as de novo in a similarly affected individual (PMID: 26633542, PS2_S). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000209116, PMID:26633542, PS1_S). A different missense change at the same codon has been reported to be associated with CLCN4 related disorder (ClinVar ID: VCV000521940, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.874, PP3_P). A missense variant is a common mechanism associated with Raynaud-Claes syndrome (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 31, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CLCN4 function (PMID: 27550844). 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) performed at Invitae indicates that this missense variant is expected to disrupt CLCN4 protein function. ClinVar contains an entry for this variant (Variation ID: 209116). This variant is also known as p.R624W. This missense change has been observed in individual(s) with CLCN4-related disease (PMID: 26633542, 27550844, 29314583). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 718 of the CLCN4 protein (p.Arg718Trp). -

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. -

See cases Uncertain:1

Uncertain significance, flagged submission

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Feb 03, 2020

ACMG classification criteria: PM2, PP2, PP5 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	.;D;D
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	.;H;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.7	D;D;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.87
MutPred		0.62		.;Gain of ubiquitination at K719 (P = 0.051);.;
MVP		1.0
MPC		2.4
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.89
gMVP		0.95

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: rs879255584; hg19: chrX-10188877;