dbSNP rs782118673: CLIC2:p.His227Leu (chrX-155277967-T-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001289.6(CLIC2):c.680A>T(p.His227Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000895 in 111,754 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H227Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Consequence

CLIC2
NM_001289.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.57

Publications

0 publications found

Variant links:

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

CLIC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.36844623).

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.680A>T	p.His227Leu	missense	Exon 6 of 6	NP_001280.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLIC2	ENST00000369449.7	TSL:1 MANE Select	c.680A>T	p.His227Leu	missense	Exon 6 of 6	ENSP00000358460.2	O15247
CLIC2	ENST00000948941.1		c.785A>T	p.His262Leu	missense	Exon 7 of 7	ENSP00000619000.1
CLIC2	ENST00000465553.5	TSL:3	n.*13A>T		downstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.00000895

AC:

AN:

111754

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000895

AC:

AN:

111754

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33916

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30753

American (AMR)

AF:

0.00

AC:

AN:

10464

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2649

East Asian (EAS)

AF:

0.00

AC:

AN:

3592

South Asian (SAS)

AF:

0.00

AC:

AN:

2675

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6003

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53190

Other (OTH)

AF:

0.00

AC:

AN:

1503

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.19

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.80

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.37

MetaSVM

Uncertain

-0.28

MutationAssessor

Benign

1.5

PhyloP100

7.6

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-3.9

REVEL

Uncertain

0.36

Sift

Benign

0.055

Sift4G

Benign

0.13

Polyphen

0.45

Vest4

0.34

MutPred

0.31

Loss of disorder (P = 0.0384)

MVP

0.98

MPC

0.89

ClinPred

0.97

GERP RS

4.9

Varity_R

0.62

gMVP

0.50

Mutation Taster

=91/9

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over