rs564438778

Positions:

• chr6-45941619-T-C
• chr6-45941619-T-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_016929.5(CLIC5):​c.334A>G​(p.Asn112Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000377 in 1,613,972 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00025 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (5 hom.)
• Consequence: CLIC5 NM_016929.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 6.21

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]

LOC124901326 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01323691).
• BP6: Variant 6-45941619-T-C is Benign according to our data. Variant chr6-45941619-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 548473.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLIC5	NM_016929.5	c.334A>G	p.Asn112Asp	missense_variant	4/6	ENST00000339561.12
LOC124901326	XR_007059604.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLIC5	ENST00000339561.12	c.334A>G	p.Asn112Asp	missense_variant	4/6	1	NM_016929.5	P1

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152068 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00500

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000684 AC: 172 AN: 251352 Hom.: 0 AF XY: 0.000994 AC XY: 135 AN XY: 135838

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00500

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000390 AC: 570 AN: 1461786 Hom.: 5 Cov.: 31 AF XY: 0.000546 AC XY: 397 AN XY: 727202

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00507

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000908

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152186 Hom.: 1 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74396

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00500

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000196 Hom.: 0

Bravo AF: 0.000151

ExAC AF: 0.000758 AC: 92

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 103 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Mar 05, 2018

- -

CLIC5-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 05, 2019

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

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 09, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	.;.;T;.;.
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;D;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.013	T;T;T;T;T
MetaSVM	Uncertain	0.42	D
MutationAssessor	Pathogenic	2.9	.;.;M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-4.6	.;.;D;D;D
REVEL	Uncertain	0.57
Sift	Benign	0.041	.;.;D;T;T
Sift4G	Uncertain	0.041	.;.;D;T;T
Polyphen		0.076	.;.;B;.;.
Vest4		0.86, 0.91, 0.87
MVP		0.97
MPC		0.30
ClinPred		0.14	T
GERP RS		5.4
Varity_R		0.83
gMVP		0.91

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

Publications

LitVar

Other links and lift over

dbSNP: rs564438778; hg19: chr6-45909356;