rs750214801

Variant names:

• chr1-24840897-A-G
• rs750214801
• NM_013943.3:c.722A>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_013943.3(CLIC4):​c.722A>G​(p.Glu241Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000379 in 1,611,466 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: CLIC4 NM_013943.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 5 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).
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.89

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.722A>G	p.Glu241Gly	missense	Exon 6 of 6	NP_039234.1	Q9Y696

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLIC4	ENST00000374379.9	TSL:1 MANE Select	c.722A>G	p.Glu241Gly	missense	Exon 6 of 6	ENSP00000363500.4	Q9Y696
	CLIC4	ENST00000488683.1	TSL:2	n.722A>G		non_coding_transcript_exon	Exon 6 of 7	ENSP00000436538.1	Q9Y696
	CLIC4	ENST00000951855.1		c.662A>G	p.Glu221Gly	missense	Exon 6 of 6	ENSP00000621914.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000121 AC: 3 AN: 248840 AF XY: 0.00000743

Gnomad AFR exome AF: 0.00

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: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000391 AC: 57 AN: 1459260 Hom.: 0 Cov.: 30 AF XY: 0.0000344 AC XY: 25 AN XY: 726016

African (AFR) AF: 0.00 AC: 0 AN: 33314

American (AMR) AF: 0.00 AC: 0 AN: 44326

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26062

East Asian (EAS) AF: 0.00 AC: 0 AN: 39496

South Asian (SAS) AF: 0.00 AC: 0 AN: 85818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000495 AC: 55 AN: 1110866

Other (OTH) AF: 0.0000166 AC: 1 AN: 60236

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74354

African (AFR) AF: 0.00 AC: 0 AN: 41440

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000386 Hom.: 0

Bravo AF: 0.0000227

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.000110

EpiControl AF: 0.00

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	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		9.3
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Pathogenic	0.80
Sift	Benign	0.31	T
Sift4G	Benign	0.28	T
Polyphen		1.0	D
Vest4		0.67
MVP		0.99
MPC		0.81
ClinPred		0.97	D
GERP RS		5.7
Varity_R		0.69
gMVP		0.70
Mutation Taster		=21/79	disease causing

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: rs750214801; hg19: chr1-25167388;