Genetic Variant NM_013943.3:c.318G>C (chr1-24827019-G-C) – 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.318G>C(p.Lys106Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CLIC4
NM_013943.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.665

Publications

0 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=0.33198398).

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.318G>C	p.Lys106Asn	missense	Exon 4 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.318G>C	p.Lys106Asn	missense	Exon 4 of 6	ENSP00000363500.4	Q9Y696
CLIC4	ENST00000488683.1	TSL:2	n.318G>C		non_coding_transcript_exon	Exon 4 of 7	ENSP00000436538.1	Q9Y696
CLIC4	ENST00000951855.1		c.258G>C	p.Lys86Asn	missense	Exon 4 of 6	ENSP00000621914.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1453172

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722954

African (AFR)

AF:

0.00

AC:

AN:

33024

American (AMR)

AF:

0.00

AC:

AN:

43116

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25890

East Asian (EAS)

AF:

0.00

AC:

AN:

39498

South Asian (SAS)

AF:

0.00

AC:

AN:

84606

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53268

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4968

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1108848

Other (OTH)

AF:

0.00

AC:

AN:

59954

GnomAD4 genome

Cov.:

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

Pathogenic

0.76

BayesDel_addAF

Uncertain

0.094

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.60

Eigen

Benign

0.074

Eigen_PC

Benign

0.059

FATHMM_MKL

Uncertain

0.86

M_CAP

Benign

0.035

MetaRNN

Benign

0.33

MetaSVM

Uncertain

0.094

MutationAssessor

Pathogenic

3.1

PhyloP100

0.67

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-4.1

REVEL

Uncertain

0.46

Sift

Uncertain

0.0090

Sift4G

Benign

0.099

Polyphen

0.77

Vest4

0.40

MutPred

0.41

Loss of ubiquitination at K106 (P = 0.0244)

MVP

0.97

MPC

0.31

ClinPred

0.98

GERP RS

1.6

Varity_R

0.87

gMVP

0.76

Mutation Taster

=43/57

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over