rs140426940

Variant names:

• chr6-31732327-C-G
• rs140426940
• NM_001288.6:c.454G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001288.6(CLIC1):​c.454G>C​(p.Val152Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 1,595,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CLIC1 NM_001288.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.17
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14593491).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001288.6. 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
	CLIC1	NM_001288.6	MANE Select	c.454G>C	p.Val152Leu	missense	Exon 5 of 6	NP_001279.2
	CLIC1	NM_001287593.1		c.454G>C	p.Val152Leu	missense	Exon 6 of 7	NP_001274522.1	O00299
	CLIC1	NM_001287594.3		c.454G>C	p.Val152Leu	missense	Exon 6 of 7	NP_001274523.1	O00299

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLIC1	ENST00000375784.8	TSL:1 MANE Select	c.454G>C	p.Val152Leu	missense	Exon 5 of 6	ENSP00000364940.3	O00299
	CLIC1	ENST00000375780.6	TSL:1	c.454G>C	p.Val152Leu	missense	Exon 6 of 7	ENSP00000364935.2	O00299
	CLIC1	ENST00000864998.1		c.463G>C	p.Val155Leu	missense	Exon 5 of 6	ENSP00000535057.1

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152192 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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

GnomAD2 exomes AF: 0.00000422 AC: 1 AN: 236732 AF XY: 0.00

Gnomad AFR exome AF: 0.0000647

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000554 AC: 8 AN: 1443314 Hom.: 0 Cov.: 31 AF XY: 0.00000418 AC XY: 3 AN XY: 717640

African (AFR) AF: 0.000214 AC: 7 AN: 32756

American (AMR) AF: 0.00 AC: 0 AN: 41220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25908

East Asian (EAS) AF: 0.00 AC: 0 AN: 38400

South Asian (SAS) AF: 0.00 AC: 0 AN: 82682

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53248

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1103644

Other (OTH) AF: 0.0000167 AC: 1 AN: 59714

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152192 Hom.: 0 Cov.: 31 AF XY: 0.0000807 AC XY: 6 AN XY: 74346

African (AFR) AF: 0.000314 AC: 13 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000718

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.21
Eigen_PC	Benign	0.034
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	0.73	N
PhyloP100		1.2
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.27
Sift	Benign	0.37	T
Sift4G	Benign	0.40	T
Polyphen		0.0010	B
Vest4		0.28
MutPred		0.42		Loss of phosphorylation at T155 (P = 0.1284)
MVP		0.89
MPC		0.46
ClinPred		0.27	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.41
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs140426940; hg19: chr6-31700104;