X-155279277-T-C

Variant names:

• chrX-155279277-T-C
• rs1557316156
• NM_001289.6:c.454A>G

Variant summary

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

The NM_001289.6(CLIC2):​c.454A>G​(p.Thr152Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,096,259 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T152N) has been classified 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: 2.87
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30002183).

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.454A>G	p.Thr152Ala	missense	Exon 5 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.454A>G	p.Thr152Ala	missense	Exon 5 of 6	ENSP00000358460.2	O15247
	CLIC2	ENST00000948941.1		c.559A>G	p.Thr187Ala	missense	Exon 6 of 7	ENSP00000619000.1
	CLIC2	ENST00000321926.4	TSL:3	c.328A>G	p.Thr110Ala	missense	Exon 4 of 4	ENSP00000318558.4	A6PVS0

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000546 AC: 1 AN: 183107 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

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: 9.12e-7 AC: 1 AN: 1096259 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 361651

African (AFR) AF: 0.00 AC: 0 AN: 26379

American (AMR) AF: 0.0000284 AC: 1 AN: 35198

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 30197

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40511

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4128

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 840336

Other (OTH) AF: 0.00 AC: 0 AN: 46033

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.33	T
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.30	T
MetaSVM	Uncertain	0.26	D
MutationAssessor	Benign	1.7	L
PhyloP100		2.9
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.24
Sift	Benign	0.21	T
Sift4G	Benign	0.12	T
Polyphen		0.049	B
Vest4		0.19
MutPred		0.31		Loss of phosphorylation at T152 (P = 0.0522)
MVP		0.98
MPC		0.60
ClinPred		0.30	T
GERP RS		4.5
Varity_R		0.36
gMVP		0.24
Mutation Taster		=72/28	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: rs1557316156; hg19: chrX-154508566;