X-155334361-G-A

Variant names:

• chrX-155334361-G-A
• rs7050330
• NM_001289.6:c.57+10C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001289.6(CLIC2):​c.57+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00274 in 1,192,179 control chromosomes in the GnomAD database, including 73 homozygotes. There are 864 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (39 hom., 422 hem., cov: 22)
  • Exomes 𝑓: 0.0016 (34 hom. 442 hem.)
• Consequence: CLIC2 NM_001289.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.267
• Publications: 0 publications found

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]

CLIC2 Gene-Disease associations (from GenCC):

• X-linked intellectual disability-cardiomegaly-congestive heart failure syndrome

  Inheritance: XL, Unknown Classification: MODERATE, SUPPORTIVE, LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, G2P
• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant X-155334361-G-A is Benign according to our data. Variant chrX-155334361-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 446044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0513 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001289.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLIC2	NM_001289.6	MANE Select	c.57+10C>T		intron	N/A	NP_001280.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLIC2	ENST00000369449.7	TSL:1 MANE Select	c.57+10C>T		intron	N/A	ENSP00000358460.2
	CLIC2	ENST00000948941.1		c.57+10C>T		intron	N/A	ENSP00000619000.1
	CLIC2	ENST00000321926.4	TSL:3	c.57+10C>T		intron	N/A	ENSP00000318558.4

Frequencies

GnomAD3 genomes AF: 0.0138 AC: 1546 AN: 111889 Hom.: 39 Cov.: 22

Gnomad AFR AF: 0.0480

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00379

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000367

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00422

Gnomad NFE AF: 0.000151

Gnomad OTH AF: 0.0112

GnomAD2 exomes AF: 0.00410 AC: 742 AN: 181095 AF XY: 0.00285

Gnomad AFR exome AF: 0.0491

Gnomad AMR exome AF: 0.00274

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000138

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.00159 AC: 1716 AN: 1080236 Hom.: 34 Cov.: 27 AF XY: 0.00127 AC XY: 442 AN XY: 348280

African (AFR) AF: 0.0536 AC: 1396 AN: 26030

American (AMR) AF: 0.00285 AC: 100 AN: 35101

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19226

East Asian (EAS) AF: 0.00 AC: 0 AN: 30140

South Asian (SAS) AF: 0.000186 AC: 10 AN: 53728

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40520

Middle Eastern (MID) AF: 0.00202 AC: 8 AN: 3953

European-Non Finnish (NFE) AF: 0.0000968 AC: 80 AN: 826095

Other (OTH) AF: 0.00268 AC: 122 AN: 45443

GnomAD4 genome AF: 0.0138 AC: 1548 AN: 111943 Hom.: 39 Cov.: 22 AF XY: 0.0123 AC XY: 422 AN XY: 34239

African (AFR) AF: 0.0480 AC: 1481 AN: 30863

American (AMR) AF: 0.00379 AC: 40 AN: 10554

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2640

East Asian (EAS) AF: 0.00 AC: 0 AN: 3515

South Asian (SAS) AF: 0.000368 AC: 1 AN: 2718

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6128

Middle Eastern (MID) AF: 0.00463 AC: 1 AN: 216

European-Non Finnish (NFE) AF: 0.000151 AC: 8 AN: 53097

Other (OTH) AF: 0.0111 AC: 17 AN: 1533

Alfa AF: 0.00421 Hom.: 68

Bravo AF: 0.0160

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	8.3
DANN	Benign	0.88
PhyloP100		0.27
PromoterAI		0.030	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7050330; hg19: chrX-154563670;