6-45903093-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016929.5(CLIC5):c.751T>G(p.Ser251Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000551 in 1,613,974 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000055 (0 hom.)
• Consequence: CLIC5 NM_016929.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.06

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.079910964).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLIC5	NM_016929.5	c.751T>G	p.Ser251Ala	missense_variant	6/6	ENST00000339561.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLIC5	ENST00000339561.12	c.751T>G	p.Ser251Ala	missense_variant	6/6	1	NM_016929.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000597 AC: 15 AN: 251316 Hom.: 0 AF XY: 0.0000736 AC XY: 10 AN XY: 135810

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000202

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: 0.0000616

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000554 AC: 81 AN: 1461820 Hom.: 0 Cov.: 30 AF XY: 0.0000564 AC XY: 41 AN XY: 727212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000201

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: 0.0000630

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152154 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74342

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.0000604

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.00

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 12, 2022

The c.1228T>G (p.S410A) alteration is located in exon 6 (coding exon 6) of the CLIC5 gene. This alteration results from a T to G substitution at nucleotide position 1228, causing the serine (S) at amino acid position 410 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 22, 2023

This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 410 of the CLIC5 protein (p.Ser410Ala). This variant is present in population databases (rs772163210, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CLIC5-related conditions. ClinVar contains an entry for this variant (Variation ID: 2351870). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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	0.16
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.049	T;.
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.67	T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.080	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;.
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.67	N;N
REVEL	Benign	0.020
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.62	P;.
Vest4		0.082
MutPred		0.21		Loss of phosphorylation at S410 (P = 0.0126);.;
MVP		0.31
MPC		0.12
ClinPred		0.11	T
GERP RS		3.4
Varity_R		0.26
gMVP		0.39

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: rs772163210; hg19: chr6-45870830;