rs587777161

Positions:

• chrX-10213734-G-A
• chrX-10213734-G-C
• chrX-10213734-G-T

Variant summary

Our verdict is Pathogenic. Variant got 23 ACMG points: 23P and 0B. PS1 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The ENST00000380833.9(CLCN4):​c.1630G>A​(p.Gly544Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G544E) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 24)
• Consequence: CLCN4 ENST00000380833.9 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.80

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 23 ACMG points.

• PS1: Transcript ENST00000380833.9 (CLCN4) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 224917
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain 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-10213735-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3024251.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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, 0.956
• PP5: Variant X-10213734-G-A is Pathogenic according to our data. Variant chrX-10213734-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 100781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-10213734-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCN4	NM_001830.4	c.1630G>A	p.Gly544Arg	missense_variant	11/13	ENST00000380833.9	NP_001821.2
CLCN4	NM_001256944.2	c.1348G>A	p.Gly450Arg	missense_variant	9/11		NP_001243873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCN4	ENST00000380833.9	c.1630G>A	p.Gly544Arg	missense_variant	11/13	1	NM_001830.4	ENSP00000370213	P4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, X-linked 49 Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	-	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.88; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000100781 / PMID: 23647072). The variant has been previously reported as de novo in a similarly affected individual (PMID: 23647072). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 04, 2022	This variant was identified as hemizygous._x000D_ Criteria applied: PS1, PS2, PM1, PS4_SUP, PM2_SUP, PP3 -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 22, 2021	Published functional studies demonstrate an almost abolishment of ClC-4 currents that lead to a damaging effect (Veeramah et al., 2013); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23647072, 27550844) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.68	D
BayesDel_noAF	Pathogenic	0.74
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	.;D;D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	.;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.6	D;D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.87
MutPred		0.75		.;Gain of solvent accessibility (P = 0.0471);.;
MVP		1.0
MPC		2.6
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.89
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs587777161; hg19: chrX-10181774; COSMIC: COSV66468819;