9-136995686-C-A

Variant summary

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

The NM_004669.3(CLIC3):​c.105G>T​(p.Lys35Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000087 in 1,609,022 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

CLIC3
NM_004669.3 missense

Scores

5
6
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.503
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]

Genome browser will be placed here

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
CLIC3NM_004669.3 linkuse as main transcriptc.105G>T p.Lys35Asn missense_variant 2/6 ENST00000494426.2 NP_004660.2 O95833

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CLIC3ENST00000494426.2 linkuse as main transcriptc.105G>T p.Lys35Asn missense_variant 2/61 NM_004669.3 ENSP00000419378.1 O95833
CLIC3ENST00000473911.1 linkuse as main transcriptn.99G>T non_coding_transcript_exon_variant 2/55
CLIC3ENST00000480181.1 linkuse as main transcriptn.62G>T non_coding_transcript_exon_variant 1/43

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152152
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000333
AC:
8
AN:
240034
Hom.:
0
AF XY:
0.0000306
AC XY:
4
AN XY:
130578
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000239
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000892
AC:
13
AN:
1456870
Hom.:
0
Cov.:
35
AF XY:
0.00000828
AC XY:
6
AN XY:
724556
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000273
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152152
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74324
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000189
ExAC
AF:
0.00000827
AC:
1

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 submitterclinical testingAmbry GeneticsAug 30, 2022The c.105G>T (p.K35N) alteration is located in exon 2 (coding exon 2) of the CLIC3 gene. This alteration results from a G to T substitution at nucleotide position 105, causing the lysine (K) at amino acid position 35 to be replaced by an asparagine (N). 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
Pathogenic
0.99
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.18
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.096
T
Eigen
Benign
0.018
Eigen_PC
Benign
-0.18
FATHMM_MKL
Benign
0.58
D
LIST_S2
Pathogenic
1.0
D
M_CAP
Uncertain
0.11
D
MetaRNN
Uncertain
0.67
D
MetaSVM
Benign
-0.53
T
MutationAssessor
Pathogenic
3.4
M
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.77
T
PROVEAN
Pathogenic
-4.7
D
REVEL
Uncertain
0.42
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.029
D
Polyphen
1.0
D
Vest4
0.64
MutPred
0.57
Loss of ubiquitination at K35 (P = 0.0224);
MVP
0.74
MPC
1.7
ClinPred
0.83
D
GERP RS
-0.39
Varity_R
0.98
gMVP
0.87

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs778515010; hg19: chr9-139890138; API