chr6-45912748-A-G

Variant names:

• chr6-45912748-A-G
• rs75878754
• NM_016929.5:c.588+1480T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 2 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):

• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive nonsyndromic hearing loss 103

  Inheritance: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016929.5. 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+1480T>C		intron	N/A	NP_058625.2	Q53G01
	CLIC5	NM_001114086.2		c.1065+1480T>C		intron	N/A	NP_001107558.1	Q9NZA1-1
	CLIC5	NM_001370650.1		c.1065+1480T>C		intron	N/A	NP_001357579.1	Q9NZA1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLIC5	ENST00000339561.12	TSL:1 MANE Select	c.588+1480T>C		intron	N/A	ENSP00000344165.6	Q9NZA1-2
	CLIC5	ENST00000185206.12	TSL:1	c.1065+1480T>C		intron	N/A	ENSP00000185206.6	Q9NZA1-1
	CLIC5	ENST00000644324.1		c.623+1030T>C		intron	N/A	ENSP00000495186.1	A0A2R8Y615

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

GnomAD2 exomes AF: 0.0233 AC: 3211 AN: 137778 AF XY: 0.0215

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 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

African (AFR) AF: 0.0347 AC: 1080 AN: 31122

American (AMR) AF: 0.0618 AC: 2203 AN: 35654

Ashkenazi Jewish (ASJ) AF: 0.0000798 AC: 2 AN: 25066

East Asian (EAS) AF: 0.0978 AC: 3485 AN: 35616

South Asian (SAS) AF: 0.0252 AC: 1984 AN: 78820

European-Finnish (FIN) AF: 0.00583 AC: 198 AN: 33934

Middle Eastern (MID) AF: 0.0113 AC: 64 AN: 5668

European-Non Finnish (NFE) AF: 0.000482 AC: 512 AN: 1063110

Other (OTH) AF: 0.00957 AC: 548 AN: 57266

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

African (AFR) AF: 0.0361 AC: 1497 AN: 41522

American (AMR) AF: 0.0513 AC: 785 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0708 AC: 367 AN: 5180

South Asian (SAS) AF: 0.0269 AC: 130 AN: 4824

European-Finnish (FIN) AF: 0.00847 AC: 90 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000720 AC: 49 AN: 68032

Other (OTH) AF: 0.0199 AC: 42 AN: 2110

Alfa AF: 0.0138 Hom.: 18

Bravo AF: 0.0220

Asia WGS AF: 0.0360 AC: 127 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	CLIC5-related disorder (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.4
DANN	Benign	0.69
PhyloP100		0.49
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs75878754; hg19: chr6-45880485;