Genetic Variant NM_016929.5:c.293C>A (chr6-45949262-G-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -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

Publications

13 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):

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

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=0.006943047).

BP6

Variant 6-45949262-G-T is Benign according to our data. Variant chr6-45949262-G-T is described in ClinVar as Benign. ClinVar VariationId is 508707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 37 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016929.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLIC5	NM_016929.5	MANE Select	c.293C>A	p.Pro98His	missense	Exon 3 of 6	NP_058625.2	Q53G01
CLIC5	NM_001114086.2		c.770C>A	p.Pro257His	missense	Exon 3 of 6	NP_001107558.1	Q9NZA1-1
CLIC5	NM_001370650.1		c.770C>A	p.Pro257His	missense	Exon 4 of 7	NP_001357579.1	Q9NZA1-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLIC5	ENST00000339561.12	TSL:1 MANE Select	c.293C>A	p.Pro98His	missense	Exon 3 of 6	ENSP00000344165.6	Q9NZA1-2
CLIC5	ENST00000185206.12	TSL:1	c.770C>A	p.Pro257His	missense	Exon 3 of 6	ENSP00000185206.6	Q9NZA1-1
CLIC5	ENST00000644324.1		c.293C>A	p.Pro98His	missense	Exon 3 of 7	ENSP00000495186.1	A0A2R8Y615

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

GnomAD2 exomes

AF:

0.0165

AC:

4143

AN:

251044

AF XY:

0.0169

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 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

African (AFR)

AF:

0.00448

AC:

150

AN:

33462

American (AMR)

AF:

0.0131

AC:

585

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.0269

AC:

702

AN:

26110

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39666

South Asian (SAS)

AF:

0.00576

AC:

496

AN:

86154

European-Finnish (FIN)

AF:

0.00891

AC:

475

AN:

53304

Middle Eastern (MID)

AF:

0.00522

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.0288

AC:

32049

AN:

1111426

Other (OTH)

AF:

0.0216

AC:

1302

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

1694

3389

5083

6778

8472

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1222

2444

3666

4888

6110

<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:

0.0171

AC:

2597

AN:

152244

Hom.:

Cov.:

AF XY:

0.0154

AC XY:

1149

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.00532

AC:

221

AN:

41534

American (AMR)

AF:

0.0176

AC:

269

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0286

AC:

AN:

3466

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00498

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00791

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0274

AC:

1864

AN:

68022

Other (OTH)

AF:

0.0137

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

127

253

380

506

633

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<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:

0.0229

Hom.:

172

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.37

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.98

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.98

MetaRNN

Benign

0.0069

MetaSVM

Benign

-0.67

MutationAssessor

Benign

2.0

PhyloP100

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-8.0

REVEL

Uncertain

0.30

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.72

MPC

0.60

ClinPred

0.047

GERP RS

5.7

Varity_R

0.89

gMVP

0.81

Mutation Taster

=56/44

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over