rs41271277

Positions:

• chr6-46080006-T-A

Variant summary

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

The NM_001114086.2(CLIC5):​c.237A>T​(p.Arg79Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00359 in 1,551,702 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (16 hom.)
• Consequence: CLIC5 NM_001114086.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.307

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0061671734).
• BP6: Variant 6-46080006-T-A is Benign according to our data. Variant chr6-46080006-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 508150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-46080006-T-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLIC5	NM_001114086.2	c.237A>T	p.Arg79Ser	missense_variant	1/6		NP_001107558.1
CLIC5	NM_001370650.1	c.237A>T	p.Arg79Ser	missense_variant	2/7		NP_001357579.1
CLIC5	XM_011514692.4	c.237A>T	p.Arg79Ser	missense_variant	1/7		XP_011512994.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLIC5	ENST00000185206.12	c.237A>T	p.Arg79Ser	missense_variant	1/6	1		ENSP00000185206.6

Frequencies

GnomAD3 genomes AF: 0.00303 AC: 461 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00452

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00497

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00273 AC: 427 AN: 156382 Hom.: 3 AF XY: 0.00276 AC XY: 229 AN XY: 82882

Gnomad AFR exome AF: 0.000757

Gnomad AMR exome AF: 0.00215

Gnomad ASJ exome AF: 0.00153

Gnomad EAS exome AF: 0.0000917

Gnomad SAS exome AF: 0.00127

Gnomad FIN exome AF: 0.000475

Gnomad NFE exome AF: 0.00498

Gnomad OTH exome AF: 0.00365

GnomAD4 exome AF: 0.00366 AC: 5115 AN: 1399394 Hom.: 16 Cov.: 34 AF XY: 0.00364 AC XY: 2512 AN XY: 690206

Gnomad4 AFR exome AF: 0.000570

Gnomad4 AMR exome AF: 0.00238

Gnomad4 ASJ exome AF: 0.00159

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.00105

Gnomad4 FIN exome AF: 0.000406

Gnomad4 NFE exome AF: 0.00433

Gnomad4 OTH exome AF: 0.00309

GnomAD4 genome AF: 0.00303 AC: 461 AN: 152308 Hom.: 0 Cov.: 32 AF XY: 0.00279 AC XY: 208 AN XY: 74466

Gnomad4 AFR AF: 0.000746

Gnomad4 AMR AF: 0.00451

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00495

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00395 Hom.: 1

Bravo AF: 0.00309

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000723 AC: 1

ESP6500EA AF: 0.00471 AC: 15

ExAC AF: 0.00266 AC: 66

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 20, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	CLIC5: BP4, BS2 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 23, 2017

p.Arg79Ser in exon 1 of CLIC5: This variant is not expected to have clinical sig nificance because it has been identified in 0.52% (46/8766) of European chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs41271277). -

Autosomal recessive nonsyndromic hearing loss 103 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Aug 07, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	7.4
DANN	Benign	0.82
DEOGEN2	Benign	0.021	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.0062	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.41	N
REVEL	Benign	0.012
Sift	Benign	0.41	T
Sift4G	Benign	0.54	T
Polyphen		0.0010	B
Vest4		0.077
MutPred		0.29		Gain of glycosylation at R79 (P = 0.0048);
MVP		0.16
MPC		0.13
ClinPred		0.00060	T
GERP RS		2.4
Varity_R		0.075
gMVP		0.091

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs41271277; hg19: chr6-46047743;