6-45914301-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_016929.5(CLIC5):c.515G>A(p.Arg172Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000773 in 1,607,210 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R172W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00098 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00075 (10 hom.)
• Consequence: CLIC5 NM_016929.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.821

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0064058304).
• BP6: Variant 6-45914301-C-T is Benign according to our data. Variant chr6-45914301-C-T is described in ClinVar as [Benign]. Clinvar id is 929957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLIC5	NM_016929.5	c.515G>A	p.Arg172Gln	missense_variant	5/6	ENST00000339561.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLIC5	ENST00000339561.12	c.515G>A	p.Arg172Gln	missense_variant	5/6	1	NM_016929.5	P1

Frequencies

GnomAD3 genomes AF: 0.000979 AC: 149 AN: 152170 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.0326

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00147 AC: 366 AN: 248992 Hom.: 3 AF XY: 0.00149 AC XY: 201 AN XY: 134528

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000209

Gnomad ASJ exome AF: 0.0303

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000300

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000300

Gnomad OTH exome AF: 0.00150

GnomAD4 exome AF: 0.000751 AC: 1093 AN: 1454922 Hom.: 10 Cov.: 31 AF XY: 0.000761 AC XY: 551 AN XY: 723768

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000248

Gnomad4 ASJ exome AF: 0.0291

Gnomad4 EAS exome AF: 0.0000506

Gnomad4 SAS exome AF: 0.000282

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000156

Gnomad4 OTH exome AF: 0.00203

GnomAD4 genome AF: 0.000978 AC: 149 AN: 152288 Hom.: 2 Cov.: 32 AF XY: 0.000833 AC XY: 62 AN XY: 74464

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.0326

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00164 Hom.: 4

Bravo AF: 0.00103

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00122 AC: 148

EpiCase AF: 0.000496

EpiControl AF: 0.000901

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 27, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Nov 20, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 13, 2019

The p.Arg331Gln variant in CLIC5 is classified as benign because it has been identified in 3% (315/10342) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). Furthermore, >5 mammals (Chinese tree shrew, Lesser Egyptian jerboa, Prarie vole, Chinese hamster, golden hamster, mouse and rat) carry a glutamine (Gln) at this position despite high nearby amino acid conservation. ACMG/AMP Criteria applied: BA1, BP4_Strong. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	18
Dann	Uncertain	0.99
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.22	N
LIST_S2	Uncertain	0.87	D;D;D;D;D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.0064	T;T;T;T;T
MetaSVM	Benign	-0.78	T
MutationTaster	Benign	0.96	N;N;N
PrimateAI	Benign	0.24	T
Polyphen		0.048	.;.;B;.;.
Vest4		0.26, 0.25, 0.27
MVP		0.93
MPC		0.14
ClinPred		0.011	T
GERP RS		4.0
Varity_R		0.32
gMVP		0.22

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: rs145681060; hg19: chr6-45882038; COSMIC: COSV51759376;