chr6-45949262-G-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_016929.5(CLIC5):c.293C>A(p.Pro98His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0238 in 1,613,118 control chromosomes in the GnomAD database, including 589 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 37 hom., cov: 32)

Exomes 𝑓: 0.024 ( 552 hom. )

Consequence

CLIC5
NM_016929.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 9.97

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006943047).

BP6

Variant 6-45949262-G-T is Benign according to our data. Variant chr6-45949262-G-T is described in ClinVar as [Benign]. Clinvar id is 508707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-45949262-G-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0171 (2597/152244) while in subpopulation NFE AF= 0.0274 (1864/68022). AF 95% confidence interval is 0.0264. There are 37 homozygotes in gnomad4. There are 1149 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 37 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLIC5	NM_016929.5 link	c.293C>A	p.Pro98His	missense_variant	Exon 3 of 6	ENST00000339561.12	NP_058625.2	Q9NZA1-2Q53G01

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLIC5	ENST00000339561.12 link	c.293C>A	p.Pro98His	missense_variant	Exon 3 of 6	1	NM_016929.5	ENSP00000344165.6		Q9NZA1-2

Frequencies

GnomAD3 genomes

AF:

0.0171

AC:

2597

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00534

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.0176

Gnomad ASJ

AF:

0.0286

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00498

Gnomad FIN

AF:

0.00791

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0274

Gnomad OTH

AF:

0.0139

GnomAD3 exomes

AF:

0.0165

AC:

4143

AN:

251044

Hom.:

AF XY:

0.0169

AC XY:

2290

AN XY:

135632

show subpopulations

Gnomad AFR exome

AF:

0.00486

Gnomad AMR exome

AF:

0.0118

Gnomad ASJ exome

AF:

0.0262

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00550

Gnomad FIN exome

AF:

0.0100

Gnomad NFE exome

AF:

0.0254

Gnomad OTH exome

AF:

0.0199

GnomAD4 exome

AF:

0.0245

AC:

35791

AN:

1460874

Hom.:

552

Cov.:

AF XY:

0.0241

AC XY:

17496

AN XY:

726698

show subpopulations

Gnomad4 AFR exome

AF:

0.00448

Gnomad4 AMR exome

AF:

0.0131

Gnomad4 ASJ exome

AF:

0.0269

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00576

Gnomad4 FIN exome

AF:

0.00891

Gnomad4 NFE exome

AF:

0.0288

Gnomad4 OTH exome

AF:

0.0216

GnomAD4 genome

AF:

0.0171

AC:

2597

AN:

152244

Hom.:

Cov.:

AF XY:

0.0154

AC XY:

1149

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.00532

Gnomad4 AMR

AF:

0.0176

Gnomad4 ASJ

AF:

0.0286

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00498

Gnomad4 FIN

AF:

0.00791

Gnomad4 NFE

AF:

0.0274

Gnomad4 OTH

AF:

0.0137

Alfa

AF:

0.0240

Hom.:

Bravo

AF:

0.0169

TwinsUK

AF:

0.0353

AC:

131

ALSPAC

AF:

0.0262

AC:

101

ESP6500AA

AF:

0.00545

AC:

ESP6500EA

AF:

0.0271

AC:

233

ExAC

AF:

0.0160

AC:

1948

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.0241

EpiControl

AF:

0.0283

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 14, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 25, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

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.Pro257His in exon 3 of CLIC5: This variant is not expected to have clinical si gnificance because it has been identified in 2.46% (1639/66532) of European chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs35822882). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.37

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

.;.;T;.;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.98

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.98

D;D;D;D;D

MetaRNN

Benign

0.0069

T;T;T;T;T

MetaSVM

Benign

-0.67

MutationAssessor

Benign

2.0

.;.;M;.;.

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-8.0

.;.;D;D;D

REVEL

Uncertain

0.30

Sift

Pathogenic

0.0

.;.;D;D;D

Sift4G

Pathogenic

0.0

.;.;D;D;D

Polyphen

1.0

.;.;D;.;.

Vest4

0.72, 0.71, 0.68

MPC

0.60

ClinPred

0.047

GERP RS

5.7

Varity_R

0.89

gMVP

0.81

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over