6-46080006-T-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001114086.2(CLIC5):c.237A>T(p.Arg79Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00359 in 1,551,702 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0037 ( 16 hom. )

Consequence

CLIC5
NM_001114086.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.307

Publications

4 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

new If you want to explore the variant's impact on the transcript NM_001114086.2, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0061671734).

BP6

Variant 6-46080006-T-A is Benign according to our data. Variant chr6-46080006-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 508150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 16 Unknown,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001114086.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLIC5	NM_001114086.2	c.237A>T	p.Arg79Ser	missense	Exon 1 of 6	NP_001107558.1	Q9NZA1-1
CLIC5	NM_001370650.1	c.237A>T	p.Arg79Ser	missense	Exon 2 of 7	NP_001357579.1	Q9NZA1-1
CLIC5	NM_001370649.1	c.-55+49498A>T		intron	N/A	NP_001357578.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLIC5	ENST00000185206.12	TSL:1	c.237A>T	p.Arg79Ser	missense	Exon 1 of 6	ENSP00000185206.6	Q9NZA1-1

Frequencies

GnomAD3 genomes

AF:

0.00303

AC:

461

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000748

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00452

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00497

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00273

AC:

427

AN:

156382

AF XY:

0.00276

show subpopulations

Gnomad AFR exome

AF:

0.000757

Gnomad AMR exome

AF:

0.00215

Gnomad ASJ exome

AF:

0.00153

Gnomad EAS exome

AF:

0.0000917

Gnomad FIN exome

AF:

0.000475

Gnomad NFE exome

AF:

0.00498

Gnomad OTH exome

AF:

0.00365

GnomAD4 exome

AF:

0.00366

AC:

5115

AN:

1399394

Hom.:

Cov.:

AF XY:

0.00364

AC XY:

2512

AN XY:

690206

show subpopulations

African (AFR)

AF:

0.000570

AC:

AN:

31598

American (AMR)

AF:

0.00238

AC:

AN:

35702

Ashkenazi Jewish (ASJ)

AF:

0.00159

AC:

AN:

25182

East Asian (EAS)

AF:

0.0000280

AC:

AN:

35738

South Asian (SAS)

AF:

0.00105

AC:

AN:

79236

European-Finnish (FIN)

AF:

0.000406

AC:

AN:

49274

Middle Eastern (MID)

AF:

0.00369

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.00433

AC:

4668

AN:

1078964

Other (OTH)

AF:

0.00309

AC:

179

AN:

58002

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

319

639

958

1278

1597

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

162

324

486

648

810

<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:

0.00303

AC:

461

AN:

152308

Hom.:

Cov.:

AF XY:

0.00279

AC XY:

208

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.000746

AC:

AN:

41580

American (AMR)

AF:

0.00451

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000622

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00495

AC:

337

AN:

68024

Other (OTH)

AF:

0.00473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

107

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00395

Hom.:

Bravo

AF:

0.00309

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Autosomal recessive nonsyndromic hearing loss 103 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.73

CADD

Benign

7.4

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.021

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.043

LIST_S2

Benign

0.38

M_CAP

Benign

0.0051

MetaRNN

Benign

0.0062

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.0

PhyloP100

0.31

PrimateAI

Benign

0.22

PROVEAN

Benign

0.41

REVEL

Benign

0.012

Sift

Benign

0.41

Sift4G

Benign

0.54

PromoterAI

0.0064

Neutral

(source)

Varity_R

0.075

gMVP

0.091

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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