rs2106801

chrX-10194954-G-AchrX-10194954-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001830.4(CLCN4):c.288G>A(p.Thr96=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,209,488 control chromosomes in the GnomAD database, including 10 homozygotes. There are 457 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T96T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0075 (9 hom., 231 hem., cov: 22)
  • Exomes 𝑓: 0.00079 (1 hom. 226 hem.)
• Consequence: CLCN4 NM_001830.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.40

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant X-10194954-G-A is Benign according to our data. Variant chrX-10194954-G-A is described in ClinVar as [Benign]. Clinvar id is 415737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.4 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00747 (832/111429) while in subpopulation AFR AF= 0.0262 (802/30621). AF 95% confidence interval is 0.0247. There are 9 homozygotes in gnomad4. There are 231 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCN4	NM_001830.4	c.288G>A	p.Thr96=	synonymous_variant	5/13	ENST00000380833.9
CLCN4	NM_001256944.2	c.6G>A	p.Thr2=	synonymous_variant	3/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCN4	ENST00000380833.9	c.288G>A	p.Thr96=	synonymous_variant	5/13	1	NM_001830.4	P4

Frequencies

GnomAD3 genomes AF: 0.00740 AC: 824 AN: 111379 Hom.: 9 Cov.: 22 AF XY: 0.00667 AC XY: 224 AN XY: 33589

Gnomad AFR AF: 0.0260

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00181

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00422

Gnomad NFE AF: 0.0000942

Gnomad OTH AF: 0.00338

GnomAD3 exomes AF: 0.00220 AC: 403 AN: 183251 Hom.: 1 AF XY: 0.00154 AC XY: 104 AN XY: 67699

Gnomad AFR exome AF: 0.0274

Gnomad AMR exome AF: 0.00120

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: 0.0000490

Gnomad OTH exome AF: 0.00110

GnomAD4 exome AF: 0.000787 AC: 864 AN: 1098059 Hom.: 1 Cov.: 31 AF XY: 0.000622 AC XY: 226 AN XY: 363421

Gnomad4 AFR exome AF: 0.0261

Gnomad4 AMR exome AF: 0.00145

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.000111

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000119

Gnomad4 OTH exome AF: 0.00228

GnomAD4 genome AF: 0.00747 AC: 832 AN: 111429 Hom.: 9 Cov.: 22 AF XY: 0.00686 AC XY: 231 AN XY: 33649

Gnomad4 AFR AF: 0.0262

Gnomad4 AMR AF: 0.00181

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000942

Gnomad4 OTH AF: 0.00334

Alfa AF: 0.00467 Hom.: 29

Bravo AF: 0.00872

EpiCase AF: 0.000328

EpiControl AF: 0.0000593

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	GeneDx	Aug 14, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 20, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	0.019
Dann	Benign	0.73

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: rs2106801; hg19: chrX-10162994;