X-10220838-G-A

Position:

chrX-10220838-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PM1PM5PP2PP3BS2

The NM_001830.4(CLCN4):c.2153G>A(p.Arg718Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000909 in 1,210,197 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R718W) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 2 hem., cov: 22)

Exomes 𝑓: 0.0000073 ( 0 hom. 0 hem. )

Consequence

CLCN4
NM_001830.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:2

Conservation

PhyloP100: 9.78

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]

CLCN4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a domain CBS 2 (size 58) in uniprot entity CLCN4_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_001830.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-10220837-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 209116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.78

BS2

High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCN4	NM_001830.4 linkuse as main transcript	c.2153G>A	p.Arg718Gln	missense_variant	12/13	ENST00000380833.9
CLCN4	NM_001256944.2 linkuse as main transcript	c.1871G>A	p.Arg624Gln	missense_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCN4	ENST00000380833.9 linkuse as main transcript	c.2153G>A	p.Arg718Gln	missense_variant	12/13	1	NM_001830.4	P4	P51793-1

Frequencies

GnomAD3 genomes

AF:

0.0000268

AC:

AN:

112147

Hom.:

Cov.:

AF XY:

0.0000583

AC XY:

AN XY:

34305

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000283

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000109

AC:

AN:

183435

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67869

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000365

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:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000729

AC:

AN:

1098050

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

363404

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000852

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:

0.00000356

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

AF:

0.0000268

AC:

AN:

112147

Hom.:

Cov.:

AF XY:

0.0000583

AC XY:

AN XY:

34305

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000283

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000106

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 06, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 718 of the CLCN4 protein (p.Arg718Gln). This variant is present in population databases (rs779824005, gnomAD 0.004%). This missense change has been observed in individual(s) with CLCN4-related conditions (PMID: 36385166). ClinVar contains an entry for this variant (Variation ID: 521940). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CLCN4 protein function. Experimental studies have shown that this missense change does not substantially affect CLCN4 function (PMID: 36385166). This variant disrupts the p.Arg718 amino acid residue in CLCN4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27550844, 29314583). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 19, 2022	Identified as a paternally inherited variant in an individual from a cohort of patients with autism spectrum disorder in published literature (Geisheker et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26034137, 28628100, 27550844, 25644381, 23647072) -

Intellectual disability, X-linked 49

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Jun 23, 2021

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 14, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

See cases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli

Dec 07, 2022

PM1_moderate;PM2_supporting;PM5_moderate;PP2_supporting;PP3_supporting;BS3_strong;B4_strong. In a subsequent segregation study, the variant was also observed in an unaffected male family member. For this reason, the variant was reclassified from likely pathogenic to likely benign -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.81

.;D;D

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.55

MetaRNN

Pathogenic

0.78

D;D;D

MetaSVM

Uncertain

0.78

MutationAssessor

Benign

1.8

.;L;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-3.2

D;D;D

REVEL

Pathogenic

0.78

Sift

Benign

0.20

T;T;T

Sift4G

Benign

0.66

T;T;T

Polyphen

0.98

.;D;.

Vest4

0.80

MutPred

0.61

.;Loss of MoRF binding (P = 0.0393);.;

MVP

0.94

MPC

2.4

ClinPred

0.80

GERP RS

5.4

Varity_R

0.65

gMVP

0.93

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over