rs143437511

Positions:

• chrX-10213862-G-A

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.1758G>A​(p.Val586=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00422 in 1,210,610 control chromosomes in the GnomAD database, including 10 homozygotes. There are 1,621 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 0.0028 (0 hom., 80 hem., cov: 24)
  • Exomes 𝑓: 0.0044 (10 hom. 1541 hem.)
• Consequence: CLCN4 NM_001830.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.420

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=-0.53).
• BP6: Variant X-10213862-G-A is Benign according to our data. Variant chrX-10213862-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 210732.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-10213862-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.42 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00276 (311/112627) while in subpopulation NFE AF= 0.00488 (260/53285). AF 95% confidence interval is 0.00439. There are 0 homozygotes in gnomad4. There are 80 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 80 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCN4	NM_001830.4	c.1758G>A	p.Val586=	synonymous_variant	11/13	ENST00000380833.9	NP_001821.2
CLCN4	NM_001256944.2	c.1476G>A	p.Val492=	synonymous_variant	9/11		NP_001243873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCN4	ENST00000380833.9	c.1758G>A	p.Val586=	synonymous_variant	11/13	1	NM_001830.4	ENSP00000370213	P4

Frequencies

GnomAD3 genomes AF: 0.00275 AC: 310 AN: 112572 Hom.: 0 Cov.: 24 AF XY: 0.00228 AC XY: 79 AN XY: 34722

Gnomad AFR AF: 0.000581

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000280

Gnomad ASJ AF: 0.00452

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000367

Gnomad FIN AF: 0.00162

Gnomad MID AF: 0.00833

Gnomad NFE AF: 0.00486

Gnomad OTH AF: 0.00328

GnomAD3 exomes AF: 0.00290 AC: 530 AN: 182910 Hom.: 1 AF XY: 0.00300 AC XY: 202 AN XY: 67426

Gnomad AFR exome AF: 0.000380

Gnomad AMR exome AF: 0.000803

Gnomad ASJ exome AF: 0.00577

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000157

Gnomad FIN exome AF: 0.00238

Gnomad NFE exome AF: 0.00496

Gnomad OTH exome AF: 0.00332

GnomAD4 exome AF: 0.00437 AC: 4793 AN: 1097983 Hom.: 10 Cov.: 31 AF XY: 0.00424 AC XY: 1541 AN XY: 363345

Gnomad4 AFR exome AF: 0.000644

Gnomad4 AMR exome AF: 0.00102

Gnomad4 ASJ exome AF: 0.00557

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000388

Gnomad4 FIN exome AF: 0.00284

Gnomad4 NFE exome AF: 0.00511

Gnomad4 OTH exome AF: 0.00371

GnomAD4 genome AF: 0.00276 AC: 311 AN: 112627 Hom.: 0 Cov.: 24 AF XY: 0.00230 AC XY: 80 AN XY: 34787

Gnomad4 AFR AF: 0.000580

Gnomad4 AMR AF: 0.000280

Gnomad4 ASJ AF: 0.00452

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000368

Gnomad4 FIN AF: 0.00162

Gnomad4 NFE AF: 0.00488

Gnomad4 OTH AF: 0.00324

Alfa AF: 0.00418 Hom.: 34

Bravo AF: 0.00241

EpiCase AF: 0.00469

EpiControl AF: 0.00534

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 12, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 19, 2018

- -

Intellectual disability, X-linked 49 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 09, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	1.6
DANN	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs143437511; hg19: chrX-10181902;