X-155280059-G-T

Variant names:

• chrX-155280059-G-T
• rs398122917
• NM_001289.6:c.303C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001289.6(CLIC2):​c.303C>A​(p.His101Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000929 in 1,076,907 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.3e-7 (0 hom. 0 hem.)
• Consequence: CLIC2 NM_001289.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.58
• 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: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, G2P
• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20362061).

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.303C>A	p.His101Gln	missense	Exon 4 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.303C>A	p.His101Gln	missense	Exon 4 of 6	ENSP00000358460.2
	CLIC2	ENST00000948941.1		c.408C>A	p.His136Gln	missense	Exon 5 of 7	ENSP00000619000.1
	CLIC2	ENST00000321926.4	TSL:3	c.177C>A	p.His59Gln	missense	Exon 3 of 4	ENSP00000318558.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.29e-7 AC: 1 AN: 1076907 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 343347

African (AFR) AF: 0.00 AC: 0 AN: 26004

American (AMR) AF: 0.00 AC: 0 AN: 35182

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19243

East Asian (EAS) AF: 0.00 AC: 0 AN: 30114

South Asian (SAS) AF: 0.00 AC: 0 AN: 53643

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40500

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4097

European-Non Finnish (NFE) AF: 0.00000122 AC: 1 AN: 822751

Other (OTH) AF: 0.00 AC: 0 AN: 45373

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	9.1
DANN	Benign	0.94
DEOGEN2	Benign	0.052	T
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.20	T
MetaSVM	Uncertain	-0.058	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		-1.6
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	0.84	N
REVEL	Benign	0.22
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.024	D
Polyphen		0.070	B
Vest4		0.25
MutPred		0.39		Gain of loop (P = 0.0097)
MVP		1.0
MPC		0.72
ClinPred		0.23	T
GERP RS		-0.29
Varity_R		0.39
gMVP		0.62
Mutation Taster		=92/8	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: rs398122917; hg19: chrX-154509348;