rs764506089

Variant names:

• chrX-10185074-G-T
• rs764506089
• NM_001830.4:c.42G>T

Variant summary

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

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.00
• 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, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.42G>T	p.Met14Ile	missense	Exon 3 of 13	NP_001821.2	P51793-1
	CLCN4	NM_001256944.2		c.-38-9837G>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.42G>T	p.Met14Ile	missense	Exon 3 of 13	ENSP00000370213.4	P51793-1
	CLCN4	ENST00000421085.7	TSL:5	c.42G>T	p.Met14Ile	missense	Exon 2 of 13	ENSP00000405754.3	A0A7I2Y1J6
	CLCN4	ENST00000888019.1		c.42G>T	p.Met14Ile	missense	Exon 3 of 13	ENSP00000558078.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000110 AC: 2 AN: 182291 AF XY: 0.0000150

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 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

African (AFR) AF: 0.00 AC: 0 AN: 26353

American (AMR) AF: 0.0000854 AC: 3 AN: 35123

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19332

East Asian (EAS) AF: 0.00 AC: 0 AN: 30170

South Asian (SAS) AF: 0.00 AC: 0 AN: 53995

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40499

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4111

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 840080

Other (OTH) AF: 0.00 AC: 0 AN: 45987

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.54	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Uncertain	0.011	D
MutationAssessor	Benign	1.4	L
PhyloP100		8.0
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.90	N
REVEL	Uncertain	0.44
Sift	Benign	0.079	T
Sift4G	Benign	0.42	T
Polyphen		0.071	B
Vest4		0.47
MutPred		0.34		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
Mutation Taster		=88/12	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: rs764506089; hg19: chrX-10153114;