6-45903233-T-G

Variant names:

• chr6-45903233-T-G
• rs200204343
• NM_016929.5:c.611A>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_016929.5(CLIC5):​c.611A>C​(p.Asn204Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000362 in 1,600,922 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: CLIC5 NM_016929.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.24

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLIC5	NM_016929.5	c.611A>C	p.Asn204Thr	missense_variant	Exon 6 of 6	ENST00000339561.12	NP_058625.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLIC5	ENST00000339561.12	c.611A>C	p.Asn204Thr	missense_variant	Exon 6 of 6	1	NM_016929.5	ENSP00000344165.6

Frequencies

GnomAD3 genomes AF: 0.0000332 AC: 5 AN: 150480 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000664

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000592

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000551 AC: 13 AN: 235970 Hom.: 0 AF XY: 0.0000551 AC XY: 7 AN XY: 127094

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000304

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000113

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000365 AC: 53 AN: 1450442 Hom.: 0 Cov.: 30 AF XY: 0.0000402 AC XY: 29 AN XY: 720534

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000462

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000416

Gnomad4 OTH exome AF: 0.0000668

GnomAD4 genome AF: 0.0000332 AC: 5 AN: 150480 Hom.: 0 Cov.: 32 AF XY: 0.0000409 AC XY: 3 AN XY: 73360

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000664

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000592

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000416

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000659 AC: 8

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

May 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1088A>C (p.N363T) alteration is located in exon 6 (coding exon 6) of the CLIC5 gene. This alteration results from a A to C substitution at nucleotide position 1088, causing the asparagine (N) at amino acid position 363 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Feb 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with threonine, which is neutral and polar, at codon 363 of the CLIC5 protein (p.Asn363Thr). This variant is present in population databases (rs200204343, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CLIC5-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	3.1	M;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.015	D;T
Sift4G	Uncertain	0.029	D;T
Polyphen		0.94	P;.
Vest4		0.62
MVP		0.98
MPC		0.55
ClinPred		0.87	D
GERP RS		5.6
Varity_R		0.64
gMVP		0.38

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: rs200204343; hg19: chr6-45870970;