X-10185053-G-A

Position:

• chrX-10185053-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001830.4(CLCN4):​c.21G>A​(p.Met7Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 22)
• Consequence: CLCN4 NM_001830.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.19

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.19388178).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCN4	NM_001830.4	c.21G>A	p.Met7Ile	missense_variant	3/13	ENST00000380833.9	NP_001821.2
CLCN4	NM_001256944.2	c.-38-9858G>A		intron_variant			NP_001243873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCN4	ENST00000380833.9	c.21G>A	p.Met7Ile	missense_variant	3/13	1	NM_001830.4	ENSP00000370213	P4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 06, 2022	Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. ClinVar contains an entry for this variant (Variation ID: 1686771). This variant has not been reported in the literature in individuals affected with CLCN4-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 7 of the CLCN4 protein (p.Met7Ile). -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 20, 2022	Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	16
DANN	Benign	0.86
DEOGEN2	Benign	0.12	T;T;.
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.79	T;T;T
M_CAP	Pathogenic	0.49	D
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	-0.32	N;.;.
MutationTaster	Benign	0.96	D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	0.44	N;N;N
REVEL	Uncertain	0.38
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.33	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.29
MutPred		0.26		Gain of catalytic residue at M7 (P = 0.0101);Gain of catalytic residue at M7 (P = 0.0101);Gain of catalytic residue at M7 (P = 0.0101);
MVP		0.82
MPC		1.3
ClinPred		0.31	T
GERP RS		4.2
Varity_R		0.29
gMVP		0.84

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-10153093;