rs192492405

chrX-10187618-C-GchrX-10187618-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001830.4(CLCN4):c.244+4C>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00157 in 1,187,563 control chromosomes in the GnomAD database, including 18 homozygotes. There are 461 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (11 hom., 219 hem., cov: 23)
  • Exomes 𝑓: 0.00086 (7 hom. 242 hem.)
• Consequence: CLCN4 NM_001830.4 splice_donor_region, intron
• Scores: Splicing: ADA: 0.0003472
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -4.41

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant X-10187618-C-G is Benign according to our data. Variant chrX-10187618-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 415733.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00836 (935/111806) while in subpopulation AFR AF= 0.0287 (882/30748). AF 95% confidence interval is 0.0271. There are 11 homozygotes in gnomad4. There are 219 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCN4	NM_001830.4	c.244+4C>G		splice_donor_region_variant, intron_variant		ENST00000380833.9
CLCN4	NM_001256944.2	c.-38-7293C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCN4	ENST00000380833.9	c.244+4C>G		splice_donor_region_variant, intron_variant		1	NM_001830.4	P4

Frequencies

GnomAD3 genomes AF: 0.00837 AC: 935 AN: 111754 Hom.: 11 Cov.: 23 AF XY: 0.00645 AC XY: 219 AN XY: 33952

Gnomad AFR AF: 0.0287

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00323

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00837

Gnomad NFE AF: 0.000169

Gnomad OTH AF: 0.00533

GnomAD3 exomes AF: 0.00245 AC: 447 AN: 182454 Hom.: 4 AF XY: 0.00148 AC XY: 99 AN XY: 67054

Gnomad AFR exome AF: 0.0299

Gnomad AMR exome AF: 0.00150

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: 0.000148

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000864 AC: 929 AN: 1075757 Hom.: 7 Cov.: 27 AF XY: 0.000707 AC XY: 242 AN XY: 342181

Gnomad4 AFR exome AF: 0.0269

Gnomad4 AMR exome AF: 0.00179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000560

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000828

Gnomad4 OTH exome AF: 0.00205

GnomAD4 genome AF: 0.00836 AC: 935 AN: 111806 Hom.: 11 Cov.: 23 AF XY: 0.00644 AC XY: 219 AN XY: 34014

Gnomad4 AFR AF: 0.0287

Gnomad4 AMR AF: 0.00323

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000169

Gnomad4 OTH AF: 0.00527

Alfa AF: 0.000655 Hom.: 5

Bravo AF: 0.00903

EpiCase AF: 0.000328

EpiControl AF: 0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 22, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
Cadd	Benign	0.0030
Dann	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00035
dbscSNV1_RF	Benign	0.024
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: rs192492405; hg19: chrX-10155658;