chr6-46079721-C-T

Variant names:

• chr6-46079721-C-T
• rs3734207
• ENST00000185206.12:c.522G>A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001114086.2(CLIC5):​c.522G>A​(p.Glu174Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.169 in 1,550,866 control chromosomes in the GnomAD database, including 25,083 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1970 hom., cov: 33)
  • Exomes 𝑓: 0.17 (23113 hom.)
• Consequence: CLIC5 NM_001114086.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.04

Genes affected

CLIC5 (HGNC:13517): (chloride intracellular channel 5) This gene encodes a member of the chloride intracellular channel (CLIC) family of chloride ion channels. The encoded protein associates with actin-based cytoskeletal structures and may play a role in multiple processes including hair cell stereocilia formation, myoblast proliferation and glomerular podocyte and endothelial cell maintenance. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 6-46079721-C-T is Benign according to our data. Variant chr6-46079721-C-T is described in ClinVar as [Benign]. Clinvar id is 508561.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.04 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.319 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLIC5	NM_001114086.2	c.522G>A	p.Glu174Glu	synonymous_variant	Exon 1 of 6		NP_001107558.1
CLIC5	NM_001370650.1	c.522G>A	p.Glu174Glu	synonymous_variant	Exon 2 of 7		NP_001357579.1
CLIC5	XM_011514692.4	c.522G>A	p.Glu174Glu	synonymous_variant	Exon 1 of 7		XP_011512994.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLIC5	ENST00000185206.12	c.522G>A	p.Glu174Glu	synonymous_variant	Exon 1 of 6	1		ENSP00000185206.6

Frequencies

GnomAD3 genomes AF: 0.140 AC: 21324 AN: 152098 Hom.: 1968 Cov.: 33

Gnomad AFR AF: 0.0517

Gnomad AMI AF: 0.181

Gnomad AMR AF: 0.127

Gnomad ASJ AF: 0.235

Gnomad EAS AF: 0.330

Gnomad SAS AF: 0.333

Gnomad FIN AF: 0.155

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.161

Gnomad OTH AF: 0.141

GnomAD3 exomes AF: 0.186 AC: 28979 AN: 155996 Hom.: 3329 AF XY: 0.198 AC XY: 16355 AN XY: 82520

Gnomad AFR exome AF: 0.0466

Gnomad AMR exome AF: 0.102

Gnomad ASJ exome AF: 0.242

Gnomad EAS exome AF: 0.317

Gnomad SAS exome AF: 0.334

Gnomad FIN exome AF: 0.147

Gnomad NFE exome AF: 0.162

Gnomad OTH exome AF: 0.178

GnomAD4 exome AF: 0.172 AC: 240325 AN: 1398650 Hom.: 23113 Cov.: 33 AF XY: 0.177 AC XY: 122074 AN XY: 689800

Gnomad4 AFR exome AF: 0.0431

Gnomad4 AMR exome AF: 0.105

Gnomad4 ASJ exome AF: 0.243

Gnomad4 EAS exome AF: 0.338

Gnomad4 SAS exome AF: 0.332

Gnomad4 FIN exome AF: 0.151

Gnomad4 NFE exome AF: 0.159

Gnomad4 OTH exome AF: 0.176

GnomAD4 genome AF: 0.140 AC: 21331 AN: 152216 Hom.: 1970 Cov.: 33 AF XY: 0.143 AC XY: 10676 AN XY: 74428

Gnomad4 AFR AF: 0.0518

Gnomad4 AMR AF: 0.127

Gnomad4 ASJ AF: 0.235

Gnomad4 EAS AF: 0.331

Gnomad4 SAS AF: 0.332

Gnomad4 FIN AF: 0.155

Gnomad4 NFE AF: 0.161

Gnomad4 OTH AF: 0.145

Alfa AF: 0.160 Hom.: 1682

Bravo AF: 0.129

Asia WGS AF: 0.336 AC: 1166 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Aug 23, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Glu174Glu in exon 1 of CLIC5: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, and has been identified in 34.27% (2608/7610) o f South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac .broadinstitute.org; dbSNP rs3734207). -

May 09, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	5.6
DANN	Benign	0.27

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3734207; hg19: chr6-46047458; COSMIC: COSV51759189;