rs779427717

Variant names:

• chr1-24814204-T-C
• rs779427717
• NM_013943.3:c.293T>C

Your query was ambiguous. Multiple possible variants found:

• chr1-24814204-T-C
• chr1-24814204-T-A
• chr1-24814204-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_013943.3(CLIC4):​c.293T>C​(p.Val98Ala) variant causes a missense change. 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: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CLIC4 NM_013943.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.10
• Publications: 2 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 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=0.27772576).

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.293T>C	p.Val98Ala	missense	Exon 3 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.293T>C	p.Val98Ala	missense	Exon 3 of 6	ENSP00000363500.4	Q9Y696
	CLIC4	ENST00000488683.1	TSL:2	n.293T>C		non_coding_transcript_exon	Exon 3 of 7	ENSP00000436538.1	Q9Y696
	CLIC4	ENST00000951855.1		c.233T>C	p.Val78Ala	missense	Exon 3 of 6	ENSP00000621914.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250376 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

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 Data not reliable, filtered out with message: AS_VQSR AF: 6.84e-7 AC: 1 AN: 1460996 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726760

African (AFR) AF: 0.00 AC: 0 AN: 33440

American (AMR) AF: 0.0000225 AC: 1 AN: 44490

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 85956

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111746

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

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	0.22
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	0.011
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.63	N
PhyloP100		5.1
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.13
Sift	Benign	0.13	T
Sift4G	Benign	0.42	T
Polyphen		0.32	B
Vest4		0.49
MutPred		0.36		Gain of disorder (P = 0.0657)
MVP		0.68
MPC		0.29
ClinPred		0.29	T
GERP RS		5.8
Varity_R		0.22
gMVP		0.61
Mutation Taster		=43/57	disease causing

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

Other links and lift over

dbSNP: rs779427717; hg19: chr1-25140695; COSMIC: COSV100978214;