rs6458477

Variant names:

• chr6-45912574-T-C
• rs6458477
• NM_016929.5:c.588+1654A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001256023.2(CLIC5):​c.*136A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 1,425,058 control chromosomes in the GnomAD database, including 12,118 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.18 (4068 hom., cov: 33)
  • Exomes 𝑓: 0.097 (8050 hom.)
• Consequence: CLIC5 NM_001256023.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.78
• Publications: 8 publications found

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):

• autosomal recessive nonsyndromic hearing loss 103

  Inheritance: Unknown, AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 6-45912574-T-C is Benign according to our data. Variant chr6-45912574-T-C is described in ClinVar as Benign. ClinVar VariationId is 1270644.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.404 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256023.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLIC5	NM_016929.5	MANE Select	c.588+1654A>G		intron	N/A	NP_058625.2	Q53G01
	CLIC5	NM_001256023.2		c.*136A>G		3_prime_UTR	Exon 6 of 6	NP_001242952.1	Q9NZA1-3
	CLIC5	NM_001114086.2		c.1065+1654A>G		intron	N/A	NP_001107558.1	Q9NZA1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLIC5	ENST00000339561.12	TSL:1 MANE Select	c.588+1654A>G		intron	N/A	ENSP00000344165.6	Q9NZA1-2
	CLIC5	ENST00000185206.12	TSL:1	c.1065+1654A>G		intron	N/A	ENSP00000185206.6	Q9NZA1-1
	CLIC5	ENST00000544153.3	TSL:2	c.*136A>G		3_prime_UTR	Exon 6 of 6	ENSP00000439195.1	Q9NZA1-3

Frequencies

GnomAD3 genomes AF: 0.182 AC: 27660 AN: 152054 Hom.: 4049 Cov.: 33

Gnomad AFR AF: 0.409

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.0432

Gnomad EAS AF: 0.134

Gnomad SAS AF: 0.149

Gnomad FIN AF: 0.0920

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.0812

Gnomad OTH AF: 0.148

GnomAD4 exome AF: 0.0966 AC: 123014 AN: 1272886 Hom.: 8050 Cov.: 18 AF XY: 0.0965 AC XY: 60432 AN XY: 626240

African (AFR) AF: 0.413 AC: 11836 AN: 28666

American (AMR) AF: 0.177 AC: 5252 AN: 29692

Ashkenazi Jewish (ASJ) AF: 0.0383 AC: 822 AN: 21490

East Asian (EAS) AF: 0.167 AC: 5618 AN: 33580

South Asian (SAS) AF: 0.135 AC: 9457 AN: 69908

European-Finnish (FIN) AF: 0.0854 AC: 2602 AN: 30462

Middle Eastern (MID) AF: 0.103 AC: 472 AN: 4580

European-Non Finnish (NFE) AF: 0.0813 AC: 81413 AN: 1001496

Other (OTH) AF: 0.105 AC: 5542 AN: 53012

GnomAD4 genome AF: 0.182 AC: 27728 AN: 152172 Hom.: 4068 Cov.: 33 AF XY: 0.183 AC XY: 13629 AN XY: 74420

African (AFR) AF: 0.409 AC: 16966 AN: 41472

American (AMR) AF: 0.153 AC: 2340 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0432 AC: 150 AN: 3470

East Asian (EAS) AF: 0.134 AC: 694 AN: 5176

South Asian (SAS) AF: 0.149 AC: 720 AN: 4834

European-Finnish (FIN) AF: 0.0920 AC: 976 AN: 10604

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.0812 AC: 5519 AN: 68004

Other (OTH) AF: 0.152 AC: 322 AN: 2116

Alfa AF: 0.114 Hom.: 2689

Bravo AF: 0.196

Asia WGS AF: 0.179 AC: 624 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.021
DANN	Benign	0.50
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6458477; hg19: chr6-45880311; COSMIC: COSV107201731;