chrX-10213862-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

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

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.420
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [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.
BS2
High Hemizygotes in GnomAd4 at 80 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CLCN4NM_001830.4 linkc.1758G>A p.Val586Val synonymous_variant 11/13 ENST00000380833.9 NP_001821.2 P51793-1
CLCN4NM_001256944.2 linkc.1476G>A p.Val492Val synonymous_variant 9/11 NP_001243873.1 P51793-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CLCN4ENST00000380833.9 linkc.1758G>A p.Val586Val synonymous_variant 11/131 NM_001830.4 ENSP00000370213.4 P51793-1

Frequencies

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

Submissions by phenotype

not provided Benign:3
Benign, criteria provided, single submitterclinical testingGeneDxDec 12, 2019- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoDec 19, 2018- -
Intellectual disability, X-linked 49 Benign:1
Likely benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsFeb 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs143437511; hg19: chrX-10181902; API