rs879255580

Variant names:

• chrX-10206437-T-G
• rs879255580
• NM_001830.4:c.635T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Moderate PP5_Moderate

The NM_001830.4(CLCN4):​c.635T>G​(p.Val212Gly) 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. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: CLCN4 NM_001830.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.85

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the CLCN4 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 25 curated pathogenic missense variants (we use a threshold of 10). The gene has 21 curated benign missense variants. Gene score misZ: 4.5166 (above the threshold of 3.09). GenCC associations: The gene is linked to non-syndromic X-linked intellectual disability, intellectual disability, X-linked 49.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.843
• PP5: Variant X-10206437-T-G is Pathogenic according to our data. Variant chrX-10206437-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 209111.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-10206437-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN4	NM_001830.4	c.635T>G	p.Val212Gly	missense_variant	Exon 7 of 13	ENST00000380833.9	NP_001821.2
CLCN4	NM_001256944.2	c.353T>G	p.Val118Gly	missense_variant	Exon 5 of 11		NP_001243873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCN4	ENST00000380833.9	c.635T>G	p.Val212Gly	missense_variant	Exon 7 of 13	1	NM_001830.4	ENSP00000370213.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

CLCN4-related disorder Pathogenic:1

Mar 22, 2016

Sydney Children's Hospital, SCHN

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Segregates with intellectual disability in family. Clinical phenotype consistent with case series of individuals with CLCN4 related disorder. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.65	D
BayesDel_noAF	Pathogenic	0.69
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	.;D;D
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.3	.;M;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.4	D;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;D
Sift4G	Benign	0.42	T;T;T
Polyphen		0.98	.;D;.
Vest4		0.64
MutPred		0.66		.;Loss of stability (P = 2e-04);Loss of stability (P = 2e-04);
MVP		1.0
MPC		2.6
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.96
gMVP		0.96

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: rs879255580; hg19: chrX-10174477;