Genetic Variant CRACR2B:p.Arg27Trp (chr11-828686-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001286606.2(CRACR2B):c.79C>T(p.Arg27Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000217 in 1,611,362 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

CRACR2B
NM_001286606.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.647

Variant links:

Genes affected

CRACR2B (HGNC:28703): (calcium release activated channel regulator 2B) Predicted to enable calcium ion binding activity. Involved in store-operated calcium entry. Predicted to be located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

CRACR2B links:

ENSG00000255108 (HGNC:):

ENSG00000255108 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11489302).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRACR2B	NM_001286606.2 link	c.79C>T	p.Arg27Trp	missense_variant	Exon 1 of 9	ENST00000525077.2	NP_001273535.1	Q8N4Y2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRACR2B	ENST00000525077.2 link	c.79C>T	p.Arg27Trp	missense_variant	Exon 1 of 9	1	NM_001286606.2	ENSP00000435299.1		Q8N4Y2-1
CRACR2B	ENST00000528542.6 link	c.79C>T	p.Arg27Trp	missense_variant	Exon 2 of 9	1		ENSP00000432334.1		Q8N4Y2-3

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000138

AC:

AN:

246260

Hom.:

AF XY:

0.000157

AC XY:

AN XY:

134094

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000890

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000466

Gnomad NFE exome

AF:

0.000260

Gnomad OTH exome

AF:

0.000168

GnomAD4 exome

AF:

0.000221

AC:

322

AN:

1459220

Hom.:

Cov.:

AF XY:

0.000211

AC XY:

153

AN XY:

726000

show subpopulations

Gnomad4 AFR exome

AF:

0.0000600

Gnomad4 AMR exome

AF:

0.0000908

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000568

Gnomad4 NFE exome

AF:

0.000272

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000177

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.000323

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000112

Hom.:

Bravo

AF:

0.000121

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.000124

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 13, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.79C>T (p.R27W) alteration is located in exon 2 (coding exon 1) of the CRACR2B gene. This alteration results from a C to T substitution at nucleotide position 79, causing the arginine (R) at amino acid position 27 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.090

T;.;.;.;.;.;T

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.070

LIST_S2

Benign

0.59

T;T;T;T;.;T;T

M_CAP

Benign

0.021

MetaRNN

Benign

0.11

T;T;T;T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

2.0

.;.;.;.;M;M;M

PrimateAI

Benign

0.29

PROVEAN

Pathogenic

-7.8

D;N;N;D;N;N;N

REVEL

Benign

0.053

Sift

Uncertain

0.018

.;D;D;D;D;D;D

Sift4G

Uncertain

0.026

D;D;D;D;D;D;D

Polyphen

0.97, 0.0

.;.;.;.;D;D;B

Vest4

0.068, 0.10

MVP

0.46

MPC

0.028

ClinPred

0.26

GERP RS

-3.6

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.1

Varity_R

0.042

gMVP

0.43

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