Genetic Variant CLIC4:p.Ser157Cys (chr1-24839914-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_013943.3(CLIC4):c.470C>G(p.Ser157Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000822 in 1,460,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

CLIC4
NM_013943.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.17

Publications

1 publications found

Variant links:

Genes affected

CLIC4 (HGNC:13518): (chloride intracellular channel 4) 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 4 (CLIC4) protein, encoded by the CLIC4 gene, is a member of the p64 family; the gene is expressed in many tissues and exhibits a intracellular vesicular pattern in Panc-1 cells (pancreatic cancer cells). [provided by RefSeq, Jul 2008]

CLIC4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.79233 (below the threshold of 3.09). Trascript score misZ: 1.1741 (below the threshold of 3.09).

BP4

Computational evidence support a benign effect (MetaRNN=0.42013007).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013943.3. 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
	CLIC4	NM_013943.3	MANE Select	c.470C>G	p.Ser157Cys	missense	Exon 5 of 6	NP_039234.1	Q9Y696

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLIC4	ENST00000374379.9	TSL:1 MANE Select	c.470C>G	p.Ser157Cys	missense	Exon 5 of 6	ENSP00000363500.4	Q9Y696
CLIC4	ENST00000488683.1	TSL:2	n.470C>G		non_coding_transcript_exon	Exon 5 of 7	ENSP00000436538.1	Q9Y696
CLIC4	ENST00000951855.1		c.410C>G	p.Ser137Cys	missense	Exon 5 of 6	ENSP00000621914.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251410

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000822

AC:

AN:

1460592

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

726610

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33442

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86200

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4788

European-Non Finnish (NFE)

AF:

0.00000989

AC:

AN:

1111930

Other (OTH)

AF:

0.00

AC:

AN:

60270

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Uncertain

0.064

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.77

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.98

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.42

MetaSVM

Pathogenic

0.88

MutationAssessor

Uncertain

2.8

PhyloP100

6.2

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.6

REVEL

Pathogenic

0.65

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0020

Polyphen

0.94

Vest4

0.39

MutPred

0.40

Loss of disorder (P = 0.0122)

MVP

0.99

MPC

0.36

ClinPred

0.88

GERP RS

5.6

Varity_R

0.56

gMVP

0.53

Mutation Taster

=52/48

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over