X-10185074-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_001830.4(CLCN4):​c.42G>T​(p.Met14Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,095,650 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)
Exomes 𝑓: 0.0000027 ( 0 hom. 1 hem. )

Consequence

CLCN4
NM_001830.4 missense

Scores

3
8
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.00
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CLCN4. . Gene score misZ 4.5166 (greater than the threshold 3.09). GenCC has associacion of gene with non-syndromic X-linked intellectual disability, intellectual disability, X-linked 49.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CLCN4NM_001830.4 linkuse as main transcriptc.42G>T p.Met14Ile missense_variant 3/13 ENST00000380833.9 NP_001821.2
CLCN4NM_001256944.2 linkuse as main transcriptc.-38-9837G>T intron_variant NP_001243873.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CLCN4ENST00000380833.9 linkuse as main transcriptc.42G>T p.Met14Ile missense_variant 3/131 NM_001830.4 ENSP00000370213 P4P51793-1

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD3 exomes
AF:
0.0000110
AC:
2
AN:
182291
Hom.:
0
AF XY:
0.0000150
AC XY:
1
AN XY:
66765
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000737
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
3
AN:
1095650
Hom.:
0
Cov.:
29
AF XY:
0.00000277
AC XY:
1
AN XY:
361088
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000854
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
23
Bravo
AF:
0.00000378
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 16, 2023ClinVar contains an entry for this variant (Variation ID: 2096319). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals affected with CLCN4-related conditions. This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 14 of the CLCN4 protein (p.Met14Ile). This variant is present in population databases (rs764506089, gnomAD 0.008%), including at least one homozygous and/or hemizygous individual. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.41
BayesDel_addAF
Uncertain
0.029
T
BayesDel_noAF
Uncertain
-0.010
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.14
T;T;.
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Pathogenic
0.98
D;D;D
M_CAP
Pathogenic
0.54
D
MetaRNN
Uncertain
0.43
T;T;T
MetaSVM
Uncertain
0.011
D
MutationAssessor
Benign
1.4
L;.;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.78
T
PROVEAN
Benign
-0.90
N;N;N
REVEL
Uncertain
0.44
Sift
Benign
0.079
T;T;D
Sift4G
Benign
0.42
T;T;D
Polyphen
0.071
B;.;.
Vest4
0.47
MutPred
0.34
Loss of disorder (P = 0.0585);Loss of disorder (P = 0.0585);Loss of disorder (P = 0.0585);
MVP
0.97
MPC
1.3
ClinPred
0.26
T
GERP RS
5.0
Varity_R
0.66
gMVP
0.95

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: rs764506089; hg19: chrX-10153114; API