rs757820245

chrX-10212628-A-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001830.4(CLCN4):c.1551A>C(p.Ala517=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000968 in 1,208,165 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 39 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 0.000045 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.00010 (0 hom. 37 hem.)
• Consequence: CLCN4 NM_001830.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.26

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant X-10212628-A-C is Benign according to our data. Variant chrX-10212628-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 415735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.26 with no splicing effect.
• BS2: High Hemizygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCN4	NM_001830.4	c.1551A>C	p.Ala517=	synonymous_variant	10/13	ENST00000380833.9
CLCN4	NM_001256944.2	c.1269A>C	p.Ala423=	synonymous_variant	8/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCN4	ENST00000380833.9	c.1551A>C	p.Ala517=	synonymous_variant	10/13	1	NM_001830.4	P4

Frequencies

GnomAD3 genomes AF: 0.0000449 AC: 5 AN: 111295 Hom.: 0 Cov.: 23 AF XY: 0.0000596 AC XY: 2 AN XY: 33529

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000284

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: 0.0000378

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000936 AC: 17 AN: 181602 Hom.: 0 AF XY: 0.0000904 AC XY: 6 AN XY: 66386

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000330

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: 0.0000990

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000102 AC: 112 AN: 1096870 Hom.: 0 Cov.: 31 AF XY: 0.000102 AC XY: 37 AN XY: 362290

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.000285

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: 0.000118

Gnomad4 OTH exome AF: 0.0000435

GnomAD4 genome AF: 0.0000449 AC: 5 AN: 111295 Hom.: 0 Cov.: 23 AF XY: 0.0000596 AC XY: 2 AN XY: 33529

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000284

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000378

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000130 Hom.: 1

Bravo AF: 0.0000793

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 06, 2023	- -

CLCN4-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 28, 2019

This variant is classified as likely 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	-0.89
Cadd	Benign	0.94
Dann	Benign	0.63

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: rs757820245; hg19: chrX-10180668;