6-46040108-A-G

Variant names:

• chr6-46040108-A-G
• rs6458486
• ENST00000185206.12:c.540+39595T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000185206.12(CLIC5):​c.540+39595T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.741 in 152,152 control chromosomes in the GnomAD database, including 42,031 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.74 (42031 hom., cov: 32)
• Consequence: CLIC5 ENST00000185206.12 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.844
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.797 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLIC5	NM_001114086.2	c.540+39595T>C		intron_variant	Intron 1 of 5		NP_001107558.1
CLIC5	NM_001370650.1	c.540+39595T>C		intron_variant	Intron 2 of 6		NP_001357579.1
CLIC5	NM_001370649.1	c.-54-84864T>C		intron_variant	Intron 1 of 5		NP_001357578.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLIC5	ENST00000185206.12	c.540+39595T>C		intron_variant	Intron 1 of 5	1		ENSP00000185206.6

Frequencies

GnomAD3 genomes AF: 0.741 AC: 112638 AN: 152034 Hom.: 41981 Cov.: 32

Gnomad AFR AF: 0.769

Gnomad AMI AF: 0.747

Gnomad AMR AF: 0.809

Gnomad ASJ AF: 0.771

Gnomad EAS AF: 0.550

Gnomad SAS AF: 0.586

Gnomad FIN AF: 0.676

Gnomad MID AF: 0.725

Gnomad NFE AF: 0.742

Gnomad OTH AF: 0.739

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.741 AC: 112742 AN: 152152 Hom.: 42031 Cov.: 32 AF XY: 0.734 AC XY: 54587 AN XY: 74376

African (AFR) AF: 0.770 AC: 31951 AN: 41512

American (AMR) AF: 0.809 AC: 12372 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.771 AC: 2675 AN: 3468

East Asian (EAS) AF: 0.551 AC: 2849 AN: 5174

South Asian (SAS) AF: 0.586 AC: 2823 AN: 4818

European-Finnish (FIN) AF: 0.676 AC: 7150 AN: 10580

Middle Eastern (MID) AF: 0.731 AC: 215 AN: 294

European-Non Finnish (NFE) AF: 0.742 AC: 50480 AN: 68000

Other (OTH) AF: 0.733 AC: 1546 AN: 2108

Alfa AF: 0.743 Hom.: 70279

Bravo AF: 0.751

Asia WGS AF: 0.580 AC: 2021 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.46
DANN	Benign	0.43
PhyloP100		-0.84
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs6458486; hg19: chr6-46007845;