NM_001830.4:c.1963A>G

Variant names:

• chrX-10214067-A-G
• rs1060502511
• NM_001830.4:c.1963A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001830.4(CLCN4):​c.1963A>G​(p.Ile655Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000947 in 1,056,006 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.5e-7 (0 hom. 0 hem.)
• Consequence: CLCN4 NM_001830.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.24

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 Uncertain_significance. Variant got 2 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3736832).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN4	NM_001830.4	c.1963A>G	p.Ile655Val	missense_variant	Exon 11 of 13	ENST00000380833.9	NP_001821.2
CLCN4	NM_001256944.2	c.1681A>G	p.Ile561Val	missense_variant	Exon 9 of 11		NP_001243873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCN4	ENST00000380833.9	c.1963A>G	p.Ile655Val	missense_variant	Exon 11 of 13	1	NM_001830.4	ENSP00000370213.4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD3 exomes AF: 0.00000707 AC: 1 AN: 141392 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 42422

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000491

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.47e-7 AC: 1 AN: 1056006 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 337654

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000351

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

Bravo AF: 0.0000340

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 655 of the CLCN4 protein (p.Ile655Val). This variant is present in population databases (no rsID available, gnomAD 0.005%). This missense change has been observed in individual(s) with CLCN4-related conditions (PMID: 36385166). ClinVar contains an entry for this variant (Variation ID: 409644). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CLCN4 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect CLCN4 function (PMID: 36385166). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	18
DANN	Benign	0.91
DEOGEN2	Benign	0.37	.;T;T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	T;T;T
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.37	T;T;T
MetaSVM	Uncertain	-0.0060	T
MutationAssessor	Benign	0.87	.;L;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	0.060	N;N;N
REVEL	Benign	0.27
Sift	Benign	0.38	T;T;T
Sift4G	Benign	0.28	T;T;T
Polyphen		0.0	.;B;.
Vest4		0.33
MutPred		0.39		.;Gain of MoRF binding (P = 0.0939);.;
MVP		0.89
MPC		0.98
ClinPred		0.16	T
GERP RS		5.7
Varity_R		0.12
gMVP		0.62

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: rs1060502511; hg19: chrX-10182107;