rs1060502511

Variant names:

• chrX-10214067-A-G
• rs1060502511
• NM_001830.4:c.1963A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001830.4(CLCN4):​c.1963A>G​(p.Ile655Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000947 in 1,056,006 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.5e-7 (0 hom. 0 hem.)
• Consequence: CLCN4 NM_001830.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.24
• 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3736832).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN4	NM_001830.4	MANE Select	c.1963A>G	p.Ile655Val	missense	Exon 11 of 13	NP_001821.2
	CLCN4	NM_001256944.2		c.1681A>G	p.Ile561Val	missense	Exon 9 of 11	NP_001243873.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN4	ENST00000380833.9	TSL:1 MANE Select	c.1963A>G	p.Ile655Val	missense	Exon 11 of 13	ENSP00000370213.4
	CLCN4	ENST00000421085.7	TSL:5	c.1987A>G	p.Ile663Val	missense	Exon 11 of 13	ENSP00000405754.3
	CLCN4	ENST00000380829.5	TSL:5	c.1870A>G	p.Ile624Val	missense	Exon 11 of 13	ENSP00000370209.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.00000707 AC: 1 AN: 141392 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000491

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: 9.47e-7 AC: 1 AN: 1056006 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 337654

African (AFR) AF: 0.00 AC: 0 AN: 24878

American (AMR) AF: 0.0000351 AC: 1 AN: 28464

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16693

East Asian (EAS) AF: 0.00 AC: 0 AN: 29760

South Asian (SAS) AF: 0.00 AC: 0 AN: 47469

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38683

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3950

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 821918

Other (OTH) AF: 0.00 AC: 0 AN: 44191

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

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	Benign	0.070
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	18
DANN	Benign	0.91
DEOGEN2	Benign	0.37	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.37	T
MetaSVM	Uncertain	-0.0060	T
MutationAssessor	Benign	0.87	L
PhyloP100		7.2
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	0.060	N
REVEL	Benign	0.27
Sift	Benign	0.38	T
Sift4G	Benign	0.28	T
Polyphen		0.0	B
Vest4		0.33
MutPred		0.39		Gain of MoRF binding (P = 0.0939)
MVP		0.89
MPC		0.98
ClinPred		0.16	T
GERP RS		5.7
Varity_R		0.12
gMVP		0.62
Mutation Taster		=78/22	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: rs1060502511; hg19: chrX-10182107;