rs747118105

Variant names:

• chrX-10214041-T-C
• rs747118105
• NM_001830.4:c.1937T>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PP2 PP3_Moderate BP6 BS2

The NM_001830.4(CLCN4):​c.1937T>C​(p.Ile646Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000176 in 1,079,046 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.000018 (0 hom. 6 hem.)
• Consequence: CLCN4 NM_001830.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 7.86

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_benign. Variant got -2 ACMG points.

• 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, 0.861
• BP6: Variant X-10214041-T-C is Benign according to our data. Variant chrX-10214041-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 409643.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}. Variant chrX-10214041-T-C is described in Lovd as [Benign].
• BS2: High Hemizygotes in GnomAdExome4 at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN4	NM_001830.4	c.1937T>C	p.Ile646Thr	missense_variant	Exon 11 of 13	ENST00000380833.9	NP_001821.2
CLCN4	NM_001256944.2	c.1655T>C	p.Ile552Thr	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.1937T>C	p.Ile646Thr	missense_variant	Exon 11 of 13	1	NM_001830.4	ENSP00000370213.4

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD3 exomes AF: 0.0000949 AC: 15 AN: 158041 Hom.: 0 AF XY: 0.0000822 AC XY: 4 AN XY: 48647

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000635

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: 0.0000176 AC: 19 AN: 1079046 Hom.: 0 Cov.: 31 AF XY: 0.0000172 AC XY: 6 AN XY: 348848

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000462

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: 0.00000240

Gnomad4 OTH exome AF: 0.0000442

GnomAD4 genome Cov.: 25

Bravo AF: 0.0000151

ExAC AF: 0.0000577 AC: 7

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Feb 01, 2017

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Dec 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.61
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	.;D;D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Uncertain	2.2	.;M;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0080	D;D;D
Sift4G	Uncertain	0.024	D;D;D
Polyphen		0.14	.;B;.
Vest4		0.83
MutPred		0.79		.;Loss of stability (P = 0.0219);.;
MVP		1.0
MPC		1.6
ClinPred		0.25	T
GERP RS		5.5
Varity_R		0.58
gMVP		0.87

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: rs747118105; hg19: chrX-10182081;