Genetic Variant NM_001289.6:c.434G>A (chrX-155279297-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_ModerateBP6_ModerateBS2

The NM_001289.6(CLIC2):c.434G>A(p.Arg145His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000704 in 1,208,034 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 27 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 0.000098 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000068 ( 0 hom. 27 hem. )

Consequence

CLIC2
NM_001289.6 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.16

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2545097).

BP6

Variant X-155279297-C-T is Benign according to our data. Variant chrX-155279297-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1321269.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAdExome4 at 27 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLIC2	NM_001289.6 link	c.434G>A	p.Arg145His	missense_variant	Exon 5 of 6	ENST00000369449.7	NP_001280.3	O15247

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CLIC2	ENST00000369449.7 link	c.434G>A	p.Arg145His	missense_variant	Exon 5 of 6	1	NM_001289.6	ENSP00000358460.2	O15247
CLIC2	ENST00000321926.4 link	c.308G>A	p.Arg103His	missense_variant	Exon 4 of 4	3		ENSP00000318558.4	A6PVS0
CLIC2	ENST00000465553.5 link	n.549G>A		non_coding_transcript_exon_variant	Exon 5 of 7	3
CLIC2	ENST00000491205.1 link	n.488G>A		non_coding_transcript_exon_variant	Exon 6 of 6	2

Frequencies

GnomAD3 genomes

AF:

0.0000982

AC:

AN:

112008

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34190

show subpopulations

Gnomad AFR

AF:

0.000195

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000280

Gnomad SAS

AF:

0.000373

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000564

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000765

AC:

AN:

182986

Hom.:

AF XY:

0.0000740

AC XY:

AN XY:

67544

show subpopulations

Gnomad AFR exome

AF:

0.000152

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000722

Gnomad SAS exome

AF:

0.000262

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000613

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000675

AC:

AN:

1095976

Hom.:

Cov.:

AF XY:

0.0000747

AC XY:

AN XY:

361382

show subpopulations

Gnomad4 AFR exome

AF:

0.000152

Gnomad4 AMR exome

AF:

0.0000284

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000993

Gnomad4 SAS exome

AF:

0.000129

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000631

Gnomad4 OTH exome

AF:

0.000109

GnomAD4 genome

AF:

0.0000982

AC:

AN:

112058

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34250

show subpopulations

Gnomad4 AFR

AF:

0.000194

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000281

Gnomad4 SAS

AF:

0.000375

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000564

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000117

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Benign:1

Oct 25, 2021

3billion, Medical Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

It is observed in the gnomAD v2.1.1 (https://gnomad.broadinstitute.org/) dataset at total allele frequency of 0.00007 with 3 hemizygotes. It is considered too common in the population to be disease-causing and also has been reported in unaffected individuals in 3billion dataset. Therfore this variant is classfiied likely benign according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.063

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.61

D;T

FATHMM_MKL

Benign

0.58

LIST_S2

Uncertain

0.93

D;D

M_CAP

Pathogenic

0.35

MetaRNN

Benign

0.25

T;T

MetaSVM

Pathogenic

0.91

MutationAssessor

Uncertain

2.8

M;.

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-3.1

D;D

REVEL

Pathogenic

0.70

Sift

Uncertain

0.012

D;D

Sift4G

Uncertain

0.021

D;D

Polyphen

1.0

D;.

Vest4

0.12

MVP

1.0

MPC

1.7

ClinPred

0.34

GERP RS

4.5

Varity_R

0.70

gMVP

0.66

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over