6-31732260-G-A

Position:

• chr6-31732260-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001288.6(CLIC1):​c.521C>T​(p.Thr174Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CLIC1 NM_001288.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

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

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLIC1	NM_001288.6	c.521C>T	p.Thr174Ile	missense_variant	5/6	ENST00000375784.8	NP_001279.2
CLIC1	NM_001287593.1	c.521C>T	p.Thr174Ile	missense_variant	6/7		NP_001274522.1
CLIC1	NM_001287594.3	c.521C>T	p.Thr174Ile	missense_variant	6/7		NP_001274523.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLIC1	ENST00000375784.8	c.521C>T	p.Thr174Ile	missense_variant	5/6	1	NM_001288.6	ENSP00000364940.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1441070 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 716454

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 30, 2024

The c.521C>T (p.T174I) alteration is located in exon 5 (coding exon 5) of the CLIC1 gene. This alteration results from a C to T substitution at nucleotide position 521, causing the threonine (T) at amino acid position 174 to be replaced by an isoleucine (I). 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	0.99
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;D;D;D;D
Eigen	Uncertain	0.59
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Uncertain	2.2	M;M;M;M;M
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.6	D;D;D;D;.
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D;D;D;.
Sift4G	Uncertain	0.023	D;D;D;D;D
Polyphen		0.46	P;P;P;P;P
Vest4		0.96
MutPred		0.84		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.97
MPC		0.98
ClinPred		0.99	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.51
gMVP		0.89

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: chr6-31700037;