1-24827100-G-T

Variant names:

• chr1-24827100-G-T
• NM_013943.3:c.399G>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_013943.3(CLIC4):​c.399G>T​(p.Arg133Ser) 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)
• Consequence: CLIC4 NM_013943.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.29

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36437196).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLIC4	NM_013943.3	c.399G>T	p.Arg133Ser	missense_variant	Exon 4 of 6	ENST00000374379.9	NP_039234.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLIC4	ENST00000374379.9	c.399G>T	p.Arg133Ser	missense_variant	Exon 4 of 6	1	NM_013943.3	ENSP00000363500.4
CLIC4	ENST00000488683.1	n.399G>T		non_coding_transcript_exon_variant	Exon 4 of 7	2		ENSP00000436538.1
CLIC4	ENST00000497755.1	n.608G>T		non_coding_transcript_exon_variant	Exon 5 of 6	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 13, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.399G>T (p.R133S) alteration is located in exon 4 (coding exon 4) of the CLIC4 gene. This alteration results from a G to T substitution at nucleotide position 399, causing the arginine (R) at amino acid position 133 to be replaced by a serine (S). 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	0.83
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	24
DANN	Benign	0.90
DEOGEN2	Uncertain	0.50	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.8	L
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.53
Sift	Benign	0.61	T
Sift4G	Benign	0.48	T
Polyphen		0.35	B
Vest4		0.53
MutPred		0.42		Gain of relative solvent accessibility (P = 0.0522);
MVP		0.96
MPC		0.26
ClinPred		0.50	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.84
gMVP		0.58

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-25153591;