X-10185042-G-T

Variant names:

• chrX-10185042-G-T
• rs1015209935
• NM_001830.4:c.10G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001830.4(CLCN4):​c.10G>T​(p.Ala4Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000183 in 1,094,508 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A4V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: CLCN4 NM_001830.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.50
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• intellectual disability, X-linked 49

  Inheritance: XL Classification: STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26125276).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001830.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN4	NM_001830.4	MANE Select	c.10G>T	p.Ala4Ser	missense	Exon 3 of 13	NP_001821.2	P51793-1
	CLCN4	NM_001256944.2		c.-38-9869G>T		intron	N/A	NP_001243873.1	P51793-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN4	ENST00000380833.9	TSL:1 MANE Select	c.10G>T	p.Ala4Ser	missense	Exon 3 of 13	ENSP00000370213.4	P51793-1
	CLCN4	ENST00000421085.7	TSL:5	c.10G>T	p.Ala4Ser	missense	Exon 2 of 13	ENSP00000405754.3	A0A7I2Y1J6
	CLCN4	ENST00000888019.1		c.10G>T	p.Ala4Ser	missense	Exon 3 of 13	ENSP00000558078.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000111 AC: 2 AN: 179392 AF XY: 0.0000156

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000373

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000227

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1094508 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 360186

African (AFR) AF: 0.00 AC: 0 AN: 26336

American (AMR) AF: 0.0000286 AC: 1 AN: 34962

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19224

East Asian (EAS) AF: 0.00 AC: 0 AN: 30147

South Asian (SAS) AF: 0.00 AC: 0 AN: 53706

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40443

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4105

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 839667

Other (OTH) AF: 0.0000218 AC: 1 AN: 45918

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	Intellectual disability, X-linked 49 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	0.69	N
PhyloP100		3.5
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.10	N
REVEL	Benign	0.28
Sift	Uncertain	0.012	D
Sift4G	Benign	0.42	T
Polyphen		0.0040	B
Vest4		0.11
MutPred		0.15		Gain of glycosylation at A4 (P = 0.0395)
MVP		0.91
MPC		1.1
ClinPred		0.17	T
GERP RS		4.2
Varity_R		0.12
gMVP		0.78
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1015209935; hg19: chrX-10153082;