6-45912742-A-G

Variant names:

• chr6-45912742-A-G
• rs75780343
• NM_016929.5:c.588+1486T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001256023.2(CLIC5):​c.589-3T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00315 in 1,529,020 control chromosomes in the GnomAD database, including 135 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0063 (29 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (106 hom.)
• Consequence: CLIC5 NM_001256023.2 splice_region, intron
• Scores: Splicing: ADA: 0.00002056
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0950

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 6-45912742-A-G is Benign according to our data. Variant chr6-45912742-A-G is described in ClinVar as [Benign]. Clinvar id is 666619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0556 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLIC5	NM_016929.5	c.588+1486T>C		intron_variant	Intron 5 of 5	ENST00000339561.12	NP_058625.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLIC5	ENST00000339561.12	c.588+1486T>C		intron_variant	Intron 5 of 5	1	NM_016929.5	ENSP00000344165.6

Frequencies

GnomAD3 genomes AF: 0.00626 AC: 953 AN: 152204 Hom.: 30 Cov.: 33

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0457

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0222

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00847

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.0136 AC: 1877 AN: 137788 AF XY: 0.0109

Gnomad AFR exome AF: 0.000751

Gnomad AMR exome AF: 0.0633

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0212

Gnomad FIN exome AF: 0.00571

Gnomad NFE exome AF: 0.0000738

Gnomad OTH exome AF: 0.00710

GnomAD4 exome AF: 0.00280 AC: 3854 AN: 1376698 Hom.: 106 Cov.: 26 AF XY: 0.00257 AC XY: 1744 AN XY: 679876

Gnomad4 AFR exome AF: 0.000350 AC: 11 AN: 31404

Gnomad4 AMR exome AF: 0.0577 AC: 2054 AN: 35618

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25142

Gnomad4 EAS exome AF: 0.0346 AC: 1236 AN: 35676

Gnomad4 SAS exome AF: 0.00116 AC: 92 AN: 79056

Gnomad4 FIN exome AF: 0.00581 AC: 197 AN: 33936

Gnomad4 NFE exome AF: 0.0000848 AC: 91 AN: 1072504

Gnomad4 Remaining exome AF: 0.00300 AC: 173 AN: 57678

GnomAD4 genome AF: 0.00628 AC: 957 AN: 152322 Hom.: 29 Cov.: 33 AF XY: 0.00787 AC XY: 586 AN XY: 74492

Gnomad4 AFR AF: 0.000409 AC: 0.000408949 AN: 0.000408949

Gnomad4 AMR AF: 0.0458 AC: 0.0457516 AN: 0.0457516

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.0226 AC: 0.0226043 AN: 0.0226043

Gnomad4 SAS AF: 0.00103 AC: 0.00103477 AN: 0.00103477

Gnomad4 FIN AF: 0.00847 AC: 0.00847298 AN: 0.00847298

Gnomad4 NFE AF: 0.000265 AC: 0.000264566 AN: 0.000264566

Gnomad4 OTH AF: 0.00473 AC: 0.00473485 AN: 0.00473485

Alfa AF: 0.00455 Hom.: 7

Bravo AF: 0.00807

Asia WGS AF: 0.00866 AC: 30 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Aug 23, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.589-3T>C in intron 5 of CLIC5: This variant is not expected to have clinical s ignificance because it has been identified in 2.78% (5/180) of Latino chromosome s by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbS NP rs75780343). -

CLIC5-related disorder Benign:1

Jul 24, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Jul 01, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.0
DANN	Benign	0.45
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000021
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.020		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: rs75780343; hg19: chr6-45880479;