NM_001288.6:c.414G>C

Variant names:

• chr6-31732367-C-G
• rs565008674
• NM_001288.6:c.414G>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.414G>C​(p.Lys138Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000441 in 1,563,778 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000043 (1 hom.)
• Consequence: CLIC1 NM_001288.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.78
• Publications: 2 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=0.13102555).

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.414G>C	p.Lys138Asn	missense	Exon 5 of 6	NP_001279.2
	CLIC1	NM_001287593.1		c.414G>C	p.Lys138Asn	missense	Exon 6 of 7	NP_001274522.1	O00299
	CLIC1	NM_001287594.3		c.414G>C	p.Lys138Asn	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.414G>C	p.Lys138Asn	missense	Exon 5 of 6	ENSP00000364940.3	O00299
	CLIC1	ENST00000375780.6	TSL:1	c.414G>C	p.Lys138Asn	missense	Exon 6 of 7	ENSP00000364935.2	O00299
	CLIC1	ENST00000864998.1		c.423G>C	p.Lys141Asn	missense	Exon 5 of 6	ENSP00000535057.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152170 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.0000328 AC: 7 AN: 213110 AF XY: 0.0000345

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000384

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000204

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000605

GnomAD4 exome AF: 0.0000432 AC: 61 AN: 1411490 Hom.: 1 Cov.: 31 AF XY: 0.0000371 AC XY: 26 AN XY: 700882

African (AFR) AF: 0.00 AC: 0 AN: 31406

American (AMR) AF: 0.0000814 AC: 3 AN: 36872

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24670

East Asian (EAS) AF: 0.000218 AC: 8 AN: 36682

South Asian (SAS) AF: 0.00 AC: 0 AN: 78138

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5516

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1087592

Other (OTH) AF: 0.000858 AC: 50 AN: 58266

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152288 Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1 AN XY: 74474

African (AFR) AF: 0.00 AC: 0 AN: 41548

American (AMR) AF: 0.0000653 AC: 1 AN: 15306

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

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000680

ExAC AF: 0.0000412 AC: 5

Asia WGS AF: 0.000577 AC: 2 AN: 3478

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	Uncertain	0.51
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.063
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.13	T
MetaSVM	Uncertain	-0.064	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		1.8
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.34
Sift	Benign	0.092	T
Sift4G	Benign	0.16	T
Polyphen		0.0030	B
Vest4		0.33
MutPred		0.42		Loss of ubiquitination at K138 (P = 0.0255)
MVP		0.94
MPC		0.61
ClinPred		0.19	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.57
gMVP		0.64
Mutation Taster		=57/43	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs565008674; hg19: chr6-31700144; COSMIC: COSV65384068; COSMIC: COSV65384068;