6-46079903-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.046 (161 hom., cov: 32)
  • Exomes 𝑓: 0.047 (1659 hom.)
• Consequence: CLIC5 ENST00000185206.12 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.780

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=0.0031041205).
• BP6: Variant 6-46079903-T-C is Benign according to our data. Variant chr6-46079903-T-C is described in ClinVar as [Benign]. Clinvar id is 508092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-46079903-T-C is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
CLIC5	NM_001114086.2	c.340A>G	p.Thr114Ala	missense_variant	1/6
CLIC5	NM_001370650.1	c.340A>G	p.Thr114Ala	missense_variant	2/7
CLIC5	XM_011514692.4	c.340A>G	p.Thr114Ala	missense_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLIC5	ENST00000185206.12	c.340A>G	p.Thr114Ala	missense_variant	1/6	1

Frequencies

GnomAD3 genomes AF: 0.0459 AC: 6979 AN: 152124 Hom.: 160 Cov.: 32

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

GnomAD3 exomes AF: 0.0433 AC: 6830 AN: 157570 Hom.: 184 AF XY: 0.0426 AC XY: 3540 AN XY: 83124

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 SAS exome AF: 0.0303

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.: 34 AF XY: 0.0467 AC XY: 32251 AN XY: 690336

Gnomad4 AFR exome AF: 0.0417

Gnomad4 AMR exome AF: 0.0343

Gnomad4 ASJ exome AF: 0.0668

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.0285

Gnomad4 FIN exome AF: 0.0629

Gnomad4 NFE exome AF: 0.0491

Gnomad4 OTH exome AF: 0.0498

GnomAD4 genome AF: 0.0459 AC: 6993 AN: 152242 Hom.: 161 Cov.: 32 AF XY: 0.0458 AC XY: 3406 AN XY: 74436

Gnomad4 AFR AF: 0.0440

Gnomad4 AMR AF: 0.0412

Gnomad4 ASJ AF: 0.0666

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0284

Gnomad4 FIN AF: 0.0585

Gnomad4 NFE AF: 0.0495

Gnomad4 OTH AF: 0.0595

Alfa AF: 0.0473 Hom.: 326

Bravo AF: 0.0451

TwinsUK AF: 0.0477 AC: 177

ALSPAC AF: 0.0462 AC: 178

ESP6500AA AF: 0.0419 AC: 58

ESP6500EA AF: 0.0456 AC: 145

ExAC AF: 0.0426 AC: 1104

Asia WGS AF: 0.0170 AC: 59 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 23, 2017	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). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 23, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.019
Dann	Benign	0.32
DEOGEN2	Benign	0.020	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0043	N
LIST_S2	Benign	0.22	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.080	N
REVEL	Benign	0.036
Sift	Benign	0.60	T
Sift4G	Benign	0.60	T
Polyphen		0.0	B
Vest4		0.014
MPC		0.11
ClinPred		0.0040	T
GERP RS		-9.3
Varity_R		0.024
gMVP		0.088

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs723580; hg19: chr6-46047640;