chrX-10213862-G-A

Variant names:

• chrX-10213862-G-A
• rs143437511
• NM_001830.4:c.1758G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001830.4(CLCN4):​c.1758G>A​(p.Val586Val) 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
• Publications: 2 publications found

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]

CLCN4 Gene-Disease associations (from GenCC):

• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• intellectual disability, X-linked 49

  Inheritance: XL Classification: STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -17 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 Benign/Likely_benign. ClinVar VariationId is 210732.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.42 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 80 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001830.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN4	NM_001830.4	MANE Select	c.1758G>A	p.Val586Val	synonymous	Exon 11 of 13	NP_001821.2	P51793-1
	CLCN4	NM_001256944.2		c.1476G>A	p.Val492Val	synonymous	Exon 9 of 11	NP_001243873.1	P51793-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN4	ENST00000380833.9	TSL:1 MANE Select	c.1758G>A	p.Val586Val	synonymous	Exon 11 of 13	ENSP00000370213.4	P51793-1
	CLCN4	ENST00000421085.7	TSL:5	c.1782G>A	p.Val594Val	synonymous	Exon 11 of 13	ENSP00000405754.3	A0A7I2Y1J6
	CLCN4	ENST00000888019.1		c.1758G>A	p.Val586Val	synonymous	Exon 11 of 13	ENSP00000558078.1

Frequencies

GnomAD3 genomes AF: 0.00275 AC: 310 AN: 112572 Hom.: 0 Cov.: 24

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

GnomAD2 exomes AF: 0.00290 AC: 530 AN: 182910 AF XY: 0.00300

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 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

African (AFR) AF: 0.000644 AC: 17 AN: 26395

American (AMR) AF: 0.00102 AC: 36 AN: 35196

Ashkenazi Jewish (ASJ) AF: 0.00557 AC: 108 AN: 19373

East Asian (EAS) AF: 0.00 AC: 0 AN: 30204

South Asian (SAS) AF: 0.000388 AC: 21 AN: 54130

European-Finnish (FIN) AF: 0.00284 AC: 115 AN: 40528

Middle Eastern (MID) AF: 0.00532 AC: 22 AN: 4136

European-Non Finnish (NFE) AF: 0.00511 AC: 4303 AN: 841938

Other (OTH) AF: 0.00371 AC: 171 AN: 46083

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

African (AFR) AF: 0.000580 AC: 18 AN: 31054

American (AMR) AF: 0.000280 AC: 3 AN: 10719

Ashkenazi Jewish (ASJ) AF: 0.00452 AC: 12 AN: 2653

East Asian (EAS) AF: 0.00 AC: 0 AN: 3560

South Asian (SAS) AF: 0.000368 AC: 1 AN: 2719

European-Finnish (FIN) AF: 0.00162 AC: 10 AN: 6190

Middle Eastern (MID) AF: 0.00913 AC: 2 AN: 219

European-Non Finnish (NFE) AF: 0.00488 AC: 260 AN: 53285

Other (OTH) AF: 0.00324 AC: 5 AN: 1545

Alfa AF: 0.00451 Hom.: 56

Bravo AF: 0.00241

EpiCase AF: 0.00469

EpiControl AF: 0.00534

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Intellectual disability, X-linked 49 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	1.6
DANN	Benign	0.80
PhyloP100		0.42
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs143437511; hg19: chrX-10181902;