Variant 6-31732367-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001288.6(CLIC1):c.414G>C(p.Lys138Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000441 in 1,563,778 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000043 ( 1 hom. )

Consequence

CLIC1
NM_001288.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.78

Variant links:

Genes affected

CLIC1 (HGNC:2062): (chloride intracellular channel 1) 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 1 is a member of the p64 family; the protein localizes principally to the cell nucleus and exhibits both nuclear and plasma membrane chloride ion channel activity. [provided by RefSeq, Jul 2008]

CLIC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13102555).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLIC1	NM_001288.6 link	c.414G>C	p.Lys138Asn	missense_variant	5/6	ENST00000375784.8	NP_001279.2	O00299Q5SRT3
CLIC1	NM_001287593.1 link	c.414G>C	p.Lys138Asn	missense_variant	6/7		NP_001274522.1	O00299Q5SRT3
CLIC1	NM_001287594.3 link	c.414G>C	p.Lys138Asn	missense_variant	6/7		NP_001274523.1	O00299Q5SRT3Q53FB0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLIC1	ENST00000375784.8 link	c.414G>C	p.Lys138Asn	missense_variant	5/6	1	NM_001288.6	ENSP00000364940.3		O00299

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152170

Hom.:

Cov.:

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:

0.000578

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.0000328

AC:

AN:

213110

Hom.:

AF XY:

0.0000345

AC XY:

AN XY:

115834

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000384

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000204

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000605

GnomAD4 exome

AF:

0.0000432

AC:

AN:

1411490

Hom.:

Cov.:

AF XY:

0.0000371

AC XY:

AN XY:

700882

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000814

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000218

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000858

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152288

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.0000412

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

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

Feb 06, 2023

The c.414G>C (p.K138N) alteration is located in exon 5 (coding exon 5) of the CLIC1 gene. This alteration results from a G to C substitution at nucleotide position 414, causing the lysine (K) at amino acid position 138 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

Uncertain

0.51

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.61

D;D;D;D;D

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.063

FATHMM_MKL

Uncertain

0.89

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.13

T;T;T;T;T

MetaSVM

Uncertain

-0.064

MutationAssessor

Uncertain

2.6

M;M;M;M;M

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.4

D;D;D;D;.

REVEL

Uncertain

0.34

Sift

Benign

0.092

T;T;T;T;.

Sift4G

Benign

0.16

T;T;T;T;T

Polyphen

0.0030

B;B;B;B;B

Vest4

0.33

MutPred

0.42

Loss of ubiquitination at K138 (P = 0.0255);Loss of ubiquitination at K138 (P = 0.0255);Loss of ubiquitination at K138 (P = 0.0255);Loss of ubiquitination at K138 (P = 0.0255);Loss of ubiquitination at K138 (P = 0.0255);

MVP

0.94

MPC

0.61

ClinPred

0.19

GERP RS

2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.57

gMVP

0.64

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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