11-829372-G-A

Variant names:

• chr11-829372-G-A
• rs781272807
• NM_001286606.2:c.290G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001286606.2(CRACR2B):​c.290G>A​(p.Gly97Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000344 in 1,454,548 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CRACR2B NM_001286606.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.91

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]

ENSG00000255108 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.757

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRACR2B	NM_001286606.2	c.290G>A	p.Gly97Glu	missense_variant	Exon 3 of 9	ENST00000525077.2	NP_001273535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRACR2B	ENST00000525077.2	c.290G>A	p.Gly97Glu	missense_variant	Exon 3 of 9	1	NM_001286606.2	ENSP00000435299.1
CRACR2B	ENST00000528542.6	c.290G>A	p.Gly97Glu	missense_variant	Exon 4 of 9	1		ENSP00000432334.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1454548 Hom.: 0 Cov.: 32 AF XY: 0.00000415 AC XY: 3 AN XY: 723556

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.290G>A (p.G97E) alteration is located in exon 4 (coding exon 3) of the CRACR2B gene. This alteration results from a G to A substitution at nucleotide position 290, causing the glycine (G) at amino acid position 97 to be replaced by a glutamic acid (E). 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	0.34
BayesDel_addAF	Uncertain	0.083	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	.;.;T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.79	.;T;T
M_CAP	Benign	0.027	D
MetaRNN	Pathogenic	0.76	D;D;D
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.3	M;M;M
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Benign	0.22
Sift	Benign	0.44	T;T;T
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		0.98	D;D;D
Vest4		0.85
MutPred		0.50		Gain of solvent accessibility (P = 0.0456);Gain of solvent accessibility (P = 0.0456);Gain of solvent accessibility (P = 0.0456);
MVP		0.49
MPC		0.16
ClinPred		0.99	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.45
gMVP		0.57

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: rs781272807; hg19: chr11-829372;