rs41304992

Positions:

• chrX-155279253-G-C

Variant summary

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

The NM_001289.6(CLIC2):​c.478C>G​(p.Pro160Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00276 in 1,206,993 control chromosomes in the GnomAD database, including 8 homozygotes. There are 1,024 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., 76 hem., cov: 23)
  • Exomes 𝑓: 0.0028 (8 hom. 948 hem.)
• Consequence: CLIC2 NM_001289.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.217

Genes affected

CLIC2 (HGNC:2063): (chloride intracellular channel 2) This gene encodes a chloride intracellular channel protein. Chloride channels are a diverse group of proteins that regulate fundamental cellular processes including stabilization of cell membrane potential, transepithelial transport, maintenance of intracellular pH, and regulation of cell volume. This protein plays a role in inhibiting the function of ryanodine receptor 2. A mutation in this gene is the cause of an X-linked form of cognitive disability. [provided by RefSeq, Jul 2017]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006031245).
• BP6: Variant X-155279253-G-C is Benign according to our data. Variant chrX-155279253-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 197724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-155279253-G-C is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd4 at 76 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLIC2	NM_001289.6	c.478C>G	p.Pro160Ala	missense_variant	5/6	ENST00000369449.7	NP_001280.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLIC2	ENST00000369449.7	c.478C>G	p.Pro160Ala	missense_variant	5/6	1	NM_001289.6	ENSP00000358460	P1
CLIC2	ENST00000321926.4	c.352C>G	p.Pro118Ala	missense_variant	4/4	3		ENSP00000318558
CLIC2	ENST00000465553.5	n.593C>G		non_coding_transcript_exon_variant	5/7	3
CLIC2	ENST00000491205.1			downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.00214 AC: 239 AN: 111938 Hom.: 0 Cov.: 23 AF XY: 0.00223 AC XY: 76 AN XY: 34108

Gnomad AFR AF: 0.000325

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00303

Gnomad ASJ AF: 0.00302

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00854

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00254

Gnomad OTH AF: 0.00133

GnomAD3 exomes AF: 0.00264 AC: 484 AN: 183149 Hom.: 1 AF XY: 0.00250 AC XY: 169 AN XY: 67675

Gnomad AFR exome AF: 0.0000761

Gnomad AMR exome AF: 0.00106

Gnomad ASJ exome AF: 0.00227

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0104

Gnomad NFE exome AF: 0.00318

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00283 AC: 3096 AN: 1095004 Hom.: 8 Cov.: 29 AF XY: 0.00263 AC XY: 948 AN XY: 360482

Gnomad4 AFR exome AF: 0.000607

Gnomad4 AMR exome AF: 0.000937

Gnomad4 ASJ exome AF: 0.00269

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0115

Gnomad4 NFE exome AF: 0.00288

Gnomad4 OTH exome AF: 0.00250

GnomAD4 genome AF: 0.00213 AC: 239 AN: 111989 Hom.: 0 Cov.: 23 AF XY: 0.00222 AC XY: 76 AN XY: 34169

Gnomad4 AFR AF: 0.000324

Gnomad4 AMR AF: 0.00303

Gnomad4 ASJ AF: 0.00302

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00854

Gnomad4 NFE AF: 0.00254

Gnomad4 OTH AF: 0.00131

Alfa AF: 0.00225 Hom.: 45

Bravo AF: 0.00162

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00346 AC: 10

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00297 AC: 20

ExAC AF: 0.00262 AC: 318

ClinVar

Significance: Benign/Likely 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	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 30, 2016	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Nov 25, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	3.1
DANN	Benign	0.34
DEOGEN2	Benign	0.15	T;T
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.0060	T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	-1.5	N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	3.0	N;N
REVEL	Benign	0.14
Sift	Benign	0.67	T;T
Sift4G	Benign	0.75	T;T
Polyphen		0.0090	B;.
Vest4		0.10
MVP		1.0
MPC		0.56
ClinPred		0.0084	T
GERP RS		0.56
Varity_R		0.11
gMVP		0.24

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: rs41304992; hg19: chrX-154508542;