6-46079903-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000185206.12(CLIC5):c.340A>G(p.Thr114Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.047 in 1,551,914 control chromosomes in the GnomAD database, including 1,820 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.046 ( 161 hom., cov: 32)

Exomes 𝑓: 0.047 ( 1659 hom. )

Consequence

CLIC5
ENST00000185206.12 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.780

Publications

12 publications found

Variant links:

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]

CLIC5 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 103
Inheritance: Unknown, AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CLIC5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0031041205).

BP6

Variant 6-46079903-T-C is Benign according to our data. Variant chr6-46079903-T-C is described in ClinVar as Benign. ClinVar VariationId is 508092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0629 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
CLIC5	NM_001114086.2 link	c.340A>G	p.Thr114Ala	missense_variant	Exon 1 of 6	NP_001107558.1	Q9NZA1-1Q53G01
CLIC5	NM_001370650.1 link	c.340A>G	p.Thr114Ala	missense_variant	Exon 2 of 7	NP_001357579.1
CLIC5	XM_011514692.4 link	c.340A>G	p.Thr114Ala	missense_variant	Exon 1 of 7	XP_011512994.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLIC5	ENST00000185206.12 link	c.340A>G	p.Thr114Ala	missense_variant	Exon 1 of 6	1		ENSP00000185206.6		Q9NZA1-1

Frequencies

GnomAD3 genomes

AF:

0.0459

AC:

6979

AN:

152124

Hom.:

160

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0438

Gnomad AMI

AF:

0.0395

Gnomad AMR

AF:

0.0412

Gnomad ASJ

AF:

0.0666

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0284

Gnomad FIN

AF:

0.0585

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0495

Gnomad OTH

AF:

0.0602

GnomAD2 exomes

AF:

0.0433

AC:

6830

AN:

157570

AF XY:

0.0426

show subpopulations

Gnomad AFR exome

AF:

0.0436

Gnomad AMR exome

AF:

0.0321

Gnomad ASJ exome

AF:

0.0652

Gnomad EAS exome

AF:

0.000275

Gnomad FIN exome

AF:

0.0665

Gnomad NFE exome

AF:

0.0508

Gnomad OTH exome

AF:

0.0451

GnomAD4 exome

AF:

0.0471

AC:

65897

AN:

1399672

Hom.:

1659

Cov.:

AF XY:

0.0467

AC XY:

32251

AN XY:

690336

show subpopulations

African (AFR)

AF:

0.0417

AC:

1317

AN:

31600

American (AMR)

AF:

0.0343

AC:

1223

AN:

35706

Ashkenazi Jewish (ASJ)

AF:

0.0668

AC:

1681

AN:

25182

East Asian (EAS)

AF:

0.000252

AC:

AN:

35738

South Asian (SAS)

AF:

0.0285

AC:

2258

AN:

79236

European-Finnish (FIN)

AF:

0.0629

AC:

3105

AN:

49382

Middle Eastern (MID)

AF:

0.0685

AC:

390

AN:

5696

European-Non Finnish (NFE)

AF:

0.0491

AC:

53022

AN:

1079024

Other (OTH)

AF:

0.0498

AC:

2892

AN:

58108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

3754

7509

11263

15018

18772

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2008

4016

6024

8032

10040

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0459

AC:

6993

AN:

152242

Hom.:

161

Cov.:

AF XY:

0.0458

AC XY:

3406

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.0440

AC:

1826

AN:

41528

American (AMR)

AF:

0.0412

AC:

630

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0666

AC:

231

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.0284

AC:

137

AN:

4822

European-Finnish (FIN)

AF:

0.0585

AC:

621

AN:

10612

Middle Eastern (MID)

AF:

0.0646

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0495

AC:

3366

AN:

68014

Other (OTH)

AF:

0.0595

AC:

126

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

341

682

1022

1363

1704

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

164

246

328

410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0467

Hom.:

415

Bravo

AF:

0.0451

TwinsUK

AF:

0.0477

AC:

177

ALSPAC

AF:

0.0462

AC:

178

ESP6500AA

AF:

0.0419

AC:

ESP6500EA

AF:

0.0456

AC:

145

ExAC

AF:

0.0426

AC:

1104

Asia WGS

AF:

0.0170

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

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. -

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.Thr114Ala in exon 1 of CLIC5: This variant is not expected to have clinical si gnificance because it has been identified in 7.59% (126/1660) of Finnish chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs723580). -

not provided

Benign:2

May 23, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 30, 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

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.019

(source)

DANN

Benign

0.32

DEOGEN2

Benign

0.020

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.0043

LIST_S2

Benign

0.22

MetaRNN

Benign

0.0031

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

PhyloP100

-0.78

PrimateAI

Benign

0.23

PROVEAN

Benign

0.080

REVEL

Benign

0.036

Sift

Benign

0.60

Sift4G

Benign

0.60

Polyphen

0.0

Vest4

0.014

MPC

0.11

ClinPred

0.0040

GERP RS

-9.3

PromoterAI

0.0021

Neutral

(source)

Varity_R

0.024

gMVP

0.088

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over