Genetic Variant CRACR2B:p.Gln165His (chr11-830022-G-C) – 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.495G>C(p.Gln165His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000012 in 1,418,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

CRACR2B
NM_001286606.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.63

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:

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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=0.24056289).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRACR2B	NM_001286606.2 link	c.495G>C	p.Gln165His	missense_variant	Exon 4 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.495G>C	p.Gln165His	missense_variant	Exon 4 of 9	1	NM_001286606.2	ENSP00000435299.1		Q8N4Y2-1
CRACR2B	ENST00000528542.6 link	c.495G>C	p.Gln165His	missense_variant	Exon 5 of 9	1		ENSP00000432334.1		Q8N4Y2-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000558

AC:

AN:

179226

Hom.:

AF XY:

0.0000101

AC XY:

AN XY:

99168

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000131

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000120

AC:

AN:

1418406

Hom.:

Cov.:

AF XY:

0.0000156

AC XY:

AN XY:

703574

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000155

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 10, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.495G>C (p.Q165H) alteration is located in exon 5 (coding exon 4) of the CRACR2B gene. This alteration results from a G to C substitution at nucleotide position 495, causing the glutamine (Q) at amino acid position 165 to be replaced by a histidine (H). 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

Uncertain

0.36

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

.;.;T

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.72

.;T;T

M_CAP

Benign

0.034

MetaRNN

Benign

0.24

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

M;M;M

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-2.5

N;N;N

REVEL

Benign

0.059

Sift

Uncertain

0.011

D;D;D

Sift4G

Benign

0.083

T;T;T

Polyphen

1.0

D;D;P

Vest4

0.34

MutPred

0.32

Loss of MoRF binding (P = 0.1112);Loss of MoRF binding (P = 0.1112);Loss of MoRF binding (P = 0.1112);

MVP

0.32

MPC

0.070

ClinPred

0.40

GERP RS

1.7

Varity_R

0.099

gMVP

0.36

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