rs2124144368

Variant names:

• chrX-155277941-C-T
• rs2124144368
• NM_001289.6:c.706G>A

Variant summary

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

The NM_001289.6(CLIC2):​c.706G>A​(p.Glu236Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,096,706 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: CLIC2 NM_001289.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.47
• Publications: 0 publications found

Genes affected

CLIC2 (HGNC:2063): (chloride intracellular channel 2) This gene encodes a chloride intracellular channel protein. Chloride channels are a diverse group of proteins that regulate fundamental cellular processes including stabilization of cell membrane potential, transepithelial transport, maintenance of intracellular pH, and regulation of cell volume. This protein plays a role in inhibiting the function of ryanodine receptor 2. A mutation in this gene is the cause of an X-linked form of cognitive disability. [provided by RefSeq, Jul 2017]

CLIC2 Gene-Disease associations (from GenCC):

• X-linked intellectual disability-cardiomegaly-congestive heart failure syndrome

  Inheritance: XL, Unknown Classification: MODERATE, SUPPORTIVE, LIMITED, NO_KNOWN Submitted by: Genomics England PanelApp, Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: NO_KNOWN Submitted by: ClinGen

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_001289.6. 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
	CLIC2	NM_001289.6	MANE Select	c.706G>A	p.Glu236Lys	missense	Exon 6 of 6	NP_001280.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLIC2	ENST00000369449.7	TSL:1 MANE Select	c.706G>A	p.Glu236Lys	missense	Exon 6 of 6	ENSP00000358460.2	O15247
	CLIC2	ENST00000948941.1		c.811G>A	p.Glu271Lys	missense	Exon 7 of 7	ENSP00000619000.1
	CLIC2	ENST00000465553.5	TSL:3	n.*39G>A		downstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1096706 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 362112

African (AFR) AF: 0.00 AC: 0 AN: 26364

American (AMR) AF: 0.00 AC: 0 AN: 35200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19375

East Asian (EAS) AF: 0.00 AC: 0 AN: 30173

South Asian (SAS) AF: 0.00 AC: 0 AN: 54102

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40501

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4133

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 840814

Other (OTH) AF: 0.00 AC: 0 AN: 46044

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

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	0.32
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.5
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.79
Sift	Benign	0.17	T
Sift4G	Benign	0.32	T
Polyphen		0.98	D
Vest4		0.55
MutPred		0.50		Gain of MoRF binding (P = 0.0188)
MVP		0.99
MPC		1.4
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.88
gMVP		0.91
Mutation Taster		=62/38	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: rs2124144368; hg19: chrX-154507230;