X-10185076-A-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PP2PP3_ModerateBP6_ModerateBS2

The NM_001830.4(CLCN4):​c.44A>T​(p.Asp15Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000365 in 1,095,777 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 23)
Exomes 𝑓: 0.0000037 ( 0 hom. 2 hem. )

Consequence

CLCN4
NM_001830.4 missense

Scores

8
8
1

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 9.14
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 Likely_benign. Variant got -3 ACMG points.

PP2
Missense variant in the CLCN4 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 25 curated pathogenic missense variants (we use a threshold of 10). The gene has 21 curated benign missense variants. Gene score misZ: 4.5166 (above the threshold of 3.09). GenCC associations: The gene is linked to non-syndromic X-linked intellectual disability, intellectual disability, X-linked 49.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.848
BP6
Variant X-10185076-A-T is Benign according to our data. Variant chrX-10185076-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 1143102.Status of the report is criteria_provided_single_submitter, 1 stars.
BS2
High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CLCN4NM_001830.4 linkc.44A>T p.Asp15Val missense_variant Exon 3 of 13 ENST00000380833.9 NP_001821.2 P51793-1
CLCN4NM_001256944.2 linkc.-38-9835A>T 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.44A>T p.Asp15Val missense_variant Exon 3 of 13 1 NM_001830.4 ENSP00000370213.4 P51793-1

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD3 exomes
AF:
0.0000165
AC:
3
AN:
182360
Hom.:
0
AF XY:
0.0000299
AC XY:
2
AN XY:
66826
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000110
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:
0.00000365
AC:
4
AN:
1095777
Hom.:
0
Cov.:
29
AF XY:
0.00000554
AC XY:
2
AN XY:
361215
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000114
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

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 04, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.61
BayesDel_addAF
Pathogenic
0.43
D
BayesDel_noAF
Pathogenic
0.60
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.59
D;T;.
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
1.0
D;D;D
M_CAP
Pathogenic
0.63
D
MetaRNN
Pathogenic
0.85
D;D;D
MetaSVM
Uncertain
0.62
D
MutationAssessor
Uncertain
2.3
M;.;.
PrimateAI
Uncertain
0.79
T
PROVEAN
Uncertain
-3.0
D;D;D
REVEL
Pathogenic
0.87
Sift
Uncertain
0.0010
D;D;D
Sift4G
Uncertain
0.048
D;D;D
Polyphen
0.48
P;.;.
Vest4
0.84
MutPred
0.50
Loss of disorder (P = 0.0365);Loss of disorder (P = 0.0365);Loss of disorder (P = 0.0365);
MVP
1.0
MPC
2.6
ClinPred
0.63
D
GERP RS
5.0
Varity_R
0.74
gMVP
0.98

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: rs1383722929; hg19: chrX-10153116; API