X-10185074-G-T

Variant names:

• chrX-10185074-G-T
• rs764506089
• NM_001830.4:c.42G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001830.4(CLCN4):​c.42G>T​(p.Met14Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,095,650 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000027 (0 hom. 1 hem.)
• Consequence: CLCN4 NM_001830.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.00

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 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN4	NM_001830.4	c.42G>T	p.Met14Ile	missense_variant	Exon 3 of 13	ENST00000380833.9	NP_001821.2
CLCN4	NM_001256944.2	c.-38-9837G>T		intron_variant	Intron 2 of 10		NP_001243873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCN4	ENST00000380833.9	c.42G>T	p.Met14Ile	missense_variant	Exon 3 of 13	1	NM_001830.4	ENSP00000370213.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000110 AC: 2 AN: 182291 Hom.: 0 AF XY: 0.0000150 AC XY: 1 AN XY: 66765

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000737

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: 0.00000274 AC: 3 AN: 1095650 Hom.: 0 Cov.: 29 AF XY: 0.00000277 AC XY: 1 AN XY: 361088

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000854

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.: 23

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Nov 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 14 of the CLCN4 protein (p.Met14Ile). This variant is present in population databases (rs764506089, gnomAD 0.008%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with CLCN4-related conditions. ClinVar contains an entry for this variant (Variation ID: 2096319). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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	Uncertain	0.41
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;T;.
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Uncertain	0.43	T;T;T
MetaSVM	Uncertain	0.011	D
MutationAssessor	Benign	1.4	L;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.90	N;N;N
REVEL	Uncertain	0.44
Sift	Benign	0.079	T;T;D
Sift4G	Benign	0.42	T;T;D
Polyphen		0.071	B;.;.
Vest4		0.47
MutPred		0.34		Loss of disorder (P = 0.0585);Loss of disorder (P = 0.0585);Loss of disorder (P = 0.0585);
MVP		0.97
MPC		1.3
ClinPred		0.26	T
GERP RS		5.0
Varity_R		0.66
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: rs764506089; hg19: chrX-10153114;