Variant 9-136994944-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004669.3(CLIC3):c.538C>A(p.Leu180Met) variant causes a missense change. The variant allele was found at a frequency of 0.00108 in 1,473,878 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00061 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 0 hom. )

Consequence

CLIC3
NM_004669.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.01

Variant links:

Genes affected

CLIC3 (HGNC:2064): (chloride intracellular channel 3) 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. Chloride intracellular channel 3 is a member of the p64 family and is predominantly localized in the nucleus and stimulates chloride ion channel activity. In addition, this protein may participate in cellular growth control, based on its association with ERK7, a member of the MAP kinase family. [provided by RefSeq, Jul 2008]

CLIC3 links:

CLIC3 (HGNC:):

CLIC3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLIC3	NM_004669.3 linkuse as main transcript	c.538C>A	p.Leu180Met	missense_variant	5/6	ENST00000494426.2	NP_004660.2	O95833

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CLIC3	ENST00000494426.2 linkuse as main transcript	c.538C>A	p.Leu180Met	missense_variant	5/6	1	NM_004669.3	ENSP00000419378.1	O95833
CLIC3	ENST00000473911.1 linkuse as main transcript	n.612C>A		non_coding_transcript_exon_variant	4/5	5
CLIC3	ENST00000480181.1 linkuse as main transcript	n.575C>A		non_coding_transcript_exon_variant	3/4	3

Frequencies

GnomAD3 genomes

AF:

0.000608

AC:

AN:

149686

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000244

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000662

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000988

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00116

Gnomad OTH

AF:

0.000482

GnomAD3 exomes

AF:

0.000541

AC:

AN:

99820

Hom.:

AF XY:

0.000535

AC XY:

AN XY:

56080

show subpopulations

Gnomad AFR exome

AF:

0.000381

Gnomad AMR exome

AF:

0.000108

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00133

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00113

AC:

1500

AN:

1324086

Hom.:

Cov.:

AF XY:

0.00111

AC XY:

724

AN XY:

651902

show subpopulations

Gnomad4 AFR exome

AF:

0.000186

Gnomad4 AMR exome

AF:

0.000173

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000397

Gnomad4 NFE exome

AF:

0.00138

Gnomad4 OTH exome

AF:

0.000625

GnomAD4 genome

AF:

0.000608

AC:

AN:

149792

Hom.:

Cov.:

AF XY:

0.000628

AC XY:

AN XY:

73250

show subpopulations

Gnomad4 AFR

AF:

0.000243

Gnomad4 AMR

AF:

0.0000662

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000988

Gnomad4 NFE

AF:

0.00116

Gnomad4 OTH

AF:

0.000477

Alfa

AF:

0.000801

Hom.:

Bravo

AF:

0.000570

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000790

AC:

ExAC

AF:

0.0000714

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2021

The c.538C>A (p.L180M) alteration is located in exon 5 (coding exon 5) of the CLIC3 gene. This alteration results from a C to A substitution at nucleotide position 538, causing the leucine (L) at amino acid position 180 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.064

BayesDel_noAF

Uncertain

0.10

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.36

Eigen

Uncertain

0.28

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.69

MetaRNN

Uncertain

0.55

MetaSVM

Pathogenic

0.95

MutationAssessor

Uncertain

2.8

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-1.8

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.55

MVP

0.85

MPC

1.5

ClinPred

0.15

GERP RS

1.4

Varity_R

0.68

gMVP

0.63

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over