rs35822882

Positions:

• chr6-45949262-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000339561.12(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 ENST00000339561.12 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 9.97

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 -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/exons	MANE	Protein	UniProt
CLIC5	NM_016929.5	c.293C>A	p.Pro98His	missense_variant	3/6	ENST00000339561.12	NP_058625.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLIC5	ENST00000339561.12	c.293C>A	p.Pro98His	missense_variant	3/6	1	NM_016929.5	ENSP00000344165	P1

Frequencies

GnomAD3 genomes AF: 0.0171 AC: 2597 AN: 152126 Hom.: 37 Cov.: 32

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.: 55 AF XY: 0.0169 AC XY: 2290 AN XY: 135632

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.: 30 AF XY: 0.0241 AC XY: 17496 AN XY: 726698

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.: 37 Cov.: 32 AF XY: 0.0154 AC XY: 1149 AN XY: 74450

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.: 95

Bravo AF: 0.0169

TwinsUK AF: 0.0353 AC: 131

ALSPAC AF: 0.0262 AC: 101

ESP6500AA AF: 0.00545 AC: 24

ESP6500EA AF: 0.0271 AC: 233

ExAC AF: 0.0160 AC: 1948

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.0241

EpiControl AF: 0.0283

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 14, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 25, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 23, 2017

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	T
BayesDel_noAF	Benign	-0.37
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	.;.;T;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
MetaRNN	Benign	0.0069	T;T;T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	2.0	.;.;M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.56	T
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	T
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

Other links and lift over

dbSNP: rs35822882; hg19: chr6-45916999;