X-10185033-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_SupportingPM2PP5

The NM_001830.4(CLCN4):ā€‹c.1A>Gā€‹(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000922 in 1,085,185 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 23)
Exomes š‘“: 9.2e-7 ( 0 hom. 0 hem. )

Consequence

CLCN4
NM_001830.4 start_lost

Scores

1
6
7

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 2.56
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 Uncertain_significance. Variant got 4 ACMG points.

PVS1
Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 18 CDS bases. Genomic position: 10185050. Lost 0.008 part of the original CDS.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant X-10185033-A-G is Pathogenic according to our data. Variant chrX-10185033-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 489100.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CLCN4NM_001830.4 linkc.1A>G p.Met1? start_lost Exon 3 of 13 ENST00000380833.9 NP_001821.2 P51793-1
CLCN4NM_001256944.2 linkc.-38-9878A>G intron_variant Intron 2 of 10 NP_001243873.1 P51793-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CLCN4ENST00000380833.9 linkc.1A>G p.Met1? start_lost Exon 3 of 13 1 NM_001830.4 ENSP00000370213.4 P51793-1

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
AF:
9.22e-7
AC:
1
AN:
1085185
Hom.:
0
Cov.:
29
AF XY:
0.00
AC XY:
0
AN XY:
352693
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.00000120
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
23
Bravo
AF:
0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxFeb 06, 2023Initiation codon variant in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge -
Intellectual disability, X-linked 49 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteJul 17, 2023Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Raynaud-Claes syndrome (MIM#300114). However, toxic gain of function has also been observed (PMID: 36385166). (I) 0110 - This gene is associated with X-linked dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance, however this is exclusive to females (PMID: 27550844). (I) 0207 - Variant is predicted to result in a loss of the canonical translation initiation codon (ATG) but an alternative initiation codon is known to exist. This variant does not affect the initiation codon of alternative transcript NM_001256944, and there are several downstream, inframe initiation codons within this transcript (NCBI, UCSC). (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes, 0 hemizygotes). (SP) 0705 - No comparable initiation codon variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. This variant has been reported as likely pathogenic, and was observed in a hemizygous male with autism, where the variant was inherited from his unaffected mother (ClinVar, personal communication). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
0.031
T
BayesDel_noAF
Benign
-0.19
CADD
Benign
18
DANN
Benign
0.97
DEOGEN2
Benign
0.15
T;T;.
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Uncertain
0.90
D;D;D
M_CAP
Uncertain
0.22
D
MetaRNN
Pathogenic
0.98
D;D;D
MetaSVM
Uncertain
-0.13
T
PROVEAN
Benign
-0.57
N;N;N
REVEL
Uncertain
0.34
Sift
Benign
0.083
T;T;T
Sift4G
Benign
0.40
T;T;T
Polyphen
0.0
B;.;.
Vest4
0.48
MutPred
0.99
Loss of solvent accessibility (P = 0.3103);Loss of solvent accessibility (P = 0.3103);Loss of solvent accessibility (P = 0.3103);
MVP
0.93
ClinPred
0.95
D
GERP RS
3.9
Varity_R
0.29
gMVP
0.92

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

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

Other links and lift over

dbSNP: rs1555973635; hg19: chrX-10153073; API