rs75878754

chr6-45912748-A-G

Variant summary

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

The NM_016929.5(CLIC5):c.588+1480T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00859 in 1,518,520 control chromosomes in the GnomAD database, including 417 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (81 hom., cov: 33)
  • Exomes 𝑓: 0.0074 (336 hom.)
• Consequence: CLIC5 NM_016929.5 intron
• Scores: Splicing: ADA: 0.00005694
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.493

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 (BayesDel_noAF=-0.85).
• BP6: Variant 6-45912748-A-G is Benign according to our data. Variant chr6-45912748-A-G is described in ClinVar as [Benign]. Clinvar id is 517543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0649 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLIC5	NM_016929.5	c.588+1480T>C		intron_variant		ENST00000339561.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLIC5	ENST00000339561.12	c.588+1480T>C		intron_variant		1	NM_016929.5	P1

Frequencies

GnomAD3 genomes AF: 0.0194 AC: 2954 AN: 152146 Hom.: 81 Cov.: 33

Gnomad AFR AF: 0.0361

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0513

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0707

Gnomad SAS AF: 0.0271

Gnomad FIN AF: 0.00847

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.0177

GnomAD3 exomes AF: 0.0233 AC: 3211 AN: 137778 Hom.: 100 AF XY: 0.0215 AC XY: 1602 AN XY: 74604

Gnomad AFR exome AF: 0.0341

Gnomad AMR exome AF: 0.0666

Gnomad ASJ exome AF: 0.000120

Gnomad EAS exome AF: 0.0625

Gnomad SAS exome AF: 0.0242

Gnomad FIN exome AF: 0.00571

Gnomad NFE exome AF: 0.000813

Gnomad OTH exome AF: 0.0166

GnomAD4 exome AF: 0.00737 AC: 10076 AN: 1366256 Hom.: 336 Cov.: 25 AF XY: 0.00762 AC XY: 5147 AN XY: 675404

Gnomad4 AFR exome AF: 0.0347

Gnomad4 AMR exome AF: 0.0618

Gnomad4 ASJ exome AF: 0.0000798

Gnomad4 EAS exome AF: 0.0978

Gnomad4 SAS exome AF: 0.0252

Gnomad4 FIN exome AF: 0.00583

Gnomad4 NFE exome AF: 0.000482

Gnomad4 OTH exome AF: 0.00957

GnomAD4 genome AF: 0.0195 AC: 2962 AN: 152264 Hom.: 81 Cov.: 33 AF XY: 0.0213 AC XY: 1585 AN XY: 74452

Gnomad4 AFR AF: 0.0361

Gnomad4 AMR AF: 0.0513

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0708

Gnomad4 SAS AF: 0.0269

Gnomad4 FIN AF: 0.00847

Gnomad4 NFE AF: 0.000720

Gnomad4 OTH AF: 0.0199

Alfa AF: 0.00767 Hom.: 3

Bravo AF: 0.0220

Asia WGS AF: 0.0360 AC: 127 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 23, 2017

c.589-9T>C in intron 5 of CLIC5: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence, and has been identified in 5.73% (11/192) of E ast Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.bro adinstitute.org; dbSNP rs75878754). -

CLIC5-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 24, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	2.4
Dann	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000057
dbscSNV1_RF	Benign	0.0
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: rs75878754; hg19: chr6-45880485;