NM_001289.6:c.478C>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001289.6(CLIC2):c.478C>G(p.Pro160Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00276 in 1,206,993 control chromosomes in the GnomAD database, including 8 homozygotes. There are 1,024 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0021 ( 0 hom., 76 hem., cov: 23)

Exomes 𝑓: 0.0028 ( 8 hom. 948 hem. )

Consequence

CLIC2
NM_001289.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.217

Publications

4 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: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, G2P
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: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006031245).

BP6

Variant X-155279253-G-C is Benign according to our data. Variant chrX-155279253-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 197724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 76 XL,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLIC2	NM_001289.6 link	c.478C>G	p.Pro160Ala	missense_variant	Exon 5 of 6	ENST00000369449.7	NP_001280.3	O15247

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CLIC2	ENST00000369449.7 link	c.478C>G	p.Pro160Ala	missense_variant	Exon 5 of 6	1	NM_001289.6	ENSP00000358460.2	O15247
CLIC2	ENST00000321926.4 link	c.352C>G	p.Pro118Ala	missense_variant	Exon 4 of 4	3		ENSP00000318558.4	A6PVS0
CLIC2	ENST00000465553.5 link	n.593C>G		non_coding_transcript_exon_variant	Exon 5 of 7	3
CLIC2	ENST00000491205.1 link	n.*16C>G		downstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.00214

AC:

239

AN:

111938

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000325

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00303

Gnomad ASJ

AF:

0.00302

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00854

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00254

Gnomad OTH

AF:

0.00133

GnomAD2 exomes

AF:

0.00264

AC:

484

AN:

183149

AF XY:

0.00250

show subpopulations

Gnomad AFR exome

AF:

0.0000761

Gnomad AMR exome

AF:

0.00106

Gnomad ASJ exome

AF:

0.00227

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0104

Gnomad NFE exome

AF:

0.00318

Gnomad OTH exome

AF:

0.00244

GnomAD4 exome

AF:

0.00283

AC:

3096

AN:

1095004

Hom.:

Cov.:

AF XY:

0.00263

AC XY:

948

AN XY:

360482

show subpopulations

African (AFR)

AF:

0.000607

AC:

AN:

26347

American (AMR)

AF:

0.000937

AC:

AN:

35202

Ashkenazi Jewish (ASJ)

AF:

0.00269

AC:

AN:

19365

East Asian (EAS)

AF:

0.00

AC:

AN:

30196

South Asian (SAS)

AF:

0.00

AC:

AN:

54063

European-Finnish (FIN)

AF:

0.0115

AC:

465

AN:

40515

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4130

European-Non Finnish (NFE)

AF:

0.00288

AC:

2415

AN:

839180

Other (OTH)

AF:

0.00250

AC:

115

AN:

46006

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

107

215

322

430

537

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

176

264

352

440

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00213

AC:

239

AN:

111989

Hom.:

Cov.:

AF XY:

0.00222

AC XY:

AN XY:

34169

show subpopulations

African (AFR)

AF:

0.000324

AC:

AN:

30822

American (AMR)

AF:

0.00303

AC:

AN:

10569

Ashkenazi Jewish (ASJ)

AF:

0.00302

AC:

AN:

2648

East Asian (EAS)

AF:

0.00

AC:

AN:

3561

South Asian (SAS)

AF:

0.00

AC:

AN:

2655

European-Finnish (FIN)

AF:

0.00854

AC:

AN:

6086

Middle Eastern (MID)

AF:

0.00

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.00254

AC:

135

AN:

53218

Other (OTH)

AF:

0.00131

AC:

AN:

1523

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00225

Hom.:

Bravo

AF:

0.00162

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00346

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00297

AC:

ExAC

AF:

0.00262

AC:

318

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Nov 30, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Nov 25, 2014

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.50

CADD

Benign

3.1

(source)

DANN

Benign

0.34

DEOGEN2

Benign

0.15

T;T

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.75

T;T

M_CAP

Benign

0.060

MetaRNN

Benign

0.0060

T;T

MetaSVM

Benign

-0.66

MutationAssessor

Benign

-1.5

N;.

PhyloP100

0.22

PrimateAI

Benign

0.37

PROVEAN

Benign

3.0

N;N

REVEL

Benign

0.14

Sift

Benign

0.67

T;T

Sift4G

Benign

0.75

T;T

Polyphen

0.0090

B;.

Vest4

0.10

MVP

1.0

MPC

0.56

ClinPred

0.0084

GERP RS

0.56

Varity_R

0.11

gMVP

0.24

Mutation Taster

=90/10

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over