rs879255582

Variant names:

• chrX-10213705-C-T
• rs879255582
• NM_001830.4:c.1601C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_001830.4(CLCN4):​c.1601C>T​(p.Ser534Leu) 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. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. S534S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 24)
• Consequence: CLCN4 NM_001830.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.75
• Publications: 3 publications found

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]

CLCN4 Gene-Disease associations (from GenCC):

• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• intellectual disability, X-linked 49

  Inheritance: XL Classification: STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001830.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant X-10213705-C-T is Pathogenic according to our data. Variant chrX-10213705-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 209113.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001830.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN4	NM_001830.4	MANE Select	c.1601C>T	p.Ser534Leu	missense	Exon 11 of 13	NP_001821.2
	CLCN4	NM_001256944.2		c.1319C>T	p.Ser440Leu	missense	Exon 9 of 11	NP_001243873.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN4	ENST00000380833.9	TSL:1 MANE Select	c.1601C>T	p.Ser534Leu	missense	Exon 11 of 13	ENSP00000370213.4
	CLCN4	ENST00000421085.7	TSL:5	c.1625C>T	p.Ser542Leu	missense	Exon 11 of 13	ENSP00000405754.3
	CLCN4	ENST00000380829.5	TSL:5	c.1508C>T	p.Ser503Leu	missense	Exon 11 of 13	ENSP00000370209.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	CLCN4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.69	D
BayesDel_noAF	Pathogenic	0.75
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.7	H
PhyloP100		7.7
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.98	D
Vest4		0.95
MutPred		0.90		Loss of catalytic residue at S534 (P = 0.0064)
MVP		1.0
MPC		2.2
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.82
gMVP		0.99
Mutation Taster		=3/97	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs879255582; hg19: chrX-10181745;