rs141271427

Positions:

• chrX-10212463-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.1390-4C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00163 in 1,207,928 control chromosomes in the GnomAD database, including 21 homozygotes. There are 508 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0083 (11 hom., 239 hem., cov: 23)
  • Exomes 𝑓: 0.00095 (10 hom. 269 hem.)
• Consequence: CLCN4 NM_001830.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00004745
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.18

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=-0.69).
• BP6: Variant X-10212463-C-T is Benign according to our data. Variant chrX-10212463-C-T is described in ClinVar as [Benign]. Clinvar id is 415738.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 = 0.00829 (928/111875) while in subpopulation AFR AF= 0.0288 (885/30714). AF 95% confidence interval is 0.0272. There are 11 homozygotes in gnomad4. There are 239 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 11 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCN4	NM_001830.4	c.1390-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000380833.9
CLCN4	NM_001256944.2	c.1108-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCN4	ENST00000380833.9	c.1390-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001830.4	P4

Frequencies

GnomAD3 genomes AF: 0.00828 AC: 926 AN: 111821 Hom.: 11 Cov.: 23 AF XY: 0.00700 AC XY: 238 AN XY: 34005

Gnomad AFR AF: 0.0288

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00263

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000941

Gnomad OTH AF: 0.00730

GnomAD3 exomes AF: 0.00247 AC: 447 AN: 181017 Hom.: 2 AF XY: 0.00147 AC XY: 97 AN XY: 65823

Gnomad AFR exome AF: 0.0299

Gnomad AMR exome AF: 0.00144

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000106

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000994

Gnomad OTH exome AF: 0.00134

GnomAD4 exome AF: 0.000949 AC: 1040 AN: 1096053 Hom.: 10 Cov.: 30 AF XY: 0.000744 AC XY: 269 AN XY: 361523

Gnomad4 AFR exome AF: 0.0321

Gnomad4 AMR exome AF: 0.00165

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000556

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000309

Gnomad4 OTH exome AF: 0.00226

GnomAD4 genome AF: 0.00829 AC: 928 AN: 111875 Hom.: 11 Cov.: 23 AF XY: 0.00702 AC XY: 239 AN XY: 34069

Gnomad4 AFR AF: 0.0288

Gnomad4 AMR AF: 0.00254

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000941

Gnomad4 OTH AF: 0.00721

Alfa AF: 0.00488 Hom.: 26

Bravo AF: 0.0102

EpiCase AF: 0.00

EpiControl AF: 0.000239

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 23, 2019	- -

CLCN4-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 07, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	5.7
DANN	Benign	0.89

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000047
dbscSNV1_RF	Benign	0.14
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: rs141271427; hg19: chrX-10180503;