rs201381518

Variant names:

• chrX-10185043-C-T
• rs201381518
• NM_001830.4:c.11C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001830.4(CLCN4):​c.11C>T​(p.Ala4Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000332 in 1,204,044 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 15 hemizygotes 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. A4S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.000034 (0 hom. 15 hem.)
• Consequence: CLCN4 NM_001830.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.28
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2571214).
• BS2: High Hemizygotes in GnomAdExome4 at 15 XL gene

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.11C>T	p.Ala4Val	missense	Exon 3 of 13	NP_001821.2	P51793-1
	CLCN4	NM_001256944.2		c.-38-9868C>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.11C>T	p.Ala4Val	missense	Exon 3 of 13	ENSP00000370213.4	P51793-1
	CLCN4	ENST00000421085.7	TSL:5	c.11C>T	p.Ala4Val	missense	Exon 2 of 13	ENSP00000405754.3	A0A7I2Y1J6
	CLCN4	ENST00000888019.1		c.11C>T	p.Ala4Val	missense	Exon 3 of 13	ENSP00000558078.1

Frequencies

GnomAD3 genomes AF: 0.0000269 AC: 3 AN: 111443 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000327

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000376

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000335 AC: 6 AN: 178859 AF XY: 0.0000472

Gnomad AFR exome AF: 0.0000764

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000734

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000499

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000339 AC: 37 AN: 1092601 Hom.: 0 Cov.: 29 AF XY: 0.0000418 AC XY: 15 AN XY: 358565

African (AFR) AF: 0.0000380 AC: 1 AN: 26290

American (AMR) AF: 0.00 AC: 0 AN: 34834

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19172

East Asian (EAS) AF: 0.0000332 AC: 1 AN: 30096

South Asian (SAS) AF: 0.00 AC: 0 AN: 53359

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40393

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4090

European-Non Finnish (NFE) AF: 0.0000382 AC: 32 AN: 838535

Other (OTH) AF: 0.0000655 AC: 3 AN: 45832

GnomAD4 genome AF: 0.0000269 AC: 3 AN: 111443 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33647

African (AFR) AF: 0.0000327 AC: 1 AN: 30594

American (AMR) AF: 0.00 AC: 0 AN: 10473

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2647

East Asian (EAS) AF: 0.00 AC: 0 AN: 3566

South Asian (SAS) AF: 0.00 AC: 0 AN: 2610

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6008

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.0000376 AC: 2 AN: 53125

Other (OTH) AF: 0.00 AC: 0 AN: 1498

Alfa AF: 0.00000885 Hom.: 0

Bravo AF: 0.0000151

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000247 AC: 3

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	0.14
BayesDel_addAF	Benign	0.010	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.60	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	1.0	L
PhyloP100		2.3
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.26
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.33	T
Polyphen		0.048	B
Vest4		0.23
MVP		0.91
MPC		1.2
ClinPred		0.066	T
GERP RS		3.1
Varity_R		0.15
gMVP		0.83
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs201381518; hg19: chrX-10153083;