chr4-26919563-G-A

Position:

• chr4-26919563-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_020860.4(STIM2):​c.211G>A​(p.Ala71Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,436 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: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: STIM2 NM_020860.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.42

Genes affected

STIM2 (HGNC:19205): (stromal interaction molecule 2) This gene is a member of the stromal interaction molecule (STIM) family and likely arose, along with related family member STIM1, from a common ancestral gene. The encoded protein functions to regulate calcium concentrations in the cytosol and endoplasmic reticulum, and is involved in the activation of plasma membrane Orai Ca(2+) entry channels. This gene initiates translation from a non-AUG (UUG) start site. A signal peptide is cleaved from the resulting protein. Multiple transcript variants result from alternative splicing. [provided by RefSeq, Dec 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.888

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STIM2	NM_020860.4	c.211G>A	p.Ala71Thr	missense_variant	2/12	ENST00000467087.7	NP_065911.3
STIM2	NM_001169118.2	c.211G>A	p.Ala71Thr	missense_variant	2/13		NP_001162589.1
STIM2	NM_001169117.2	c.211G>A	p.Ala71Thr	missense_variant	2/13		NP_001162588.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STIM2	ENST00000467087.7	c.211G>A	p.Ala71Thr	missense_variant	2/12	1	NM_020860.4	ENSP00000419073.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461436 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727020

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2021

The c.211G>A (p.A71T) alteration is located in exon 2 (coding exon 2) of the STIM2 gene. This alteration results from a G to A substitution at nucleotide position 211, causing the alanine (A) at amino acid position 71 to be replaced by a threonine (T). 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	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	.;.;.;T;D;D;.;D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Uncertain	2.1	.;.;.;.;.;M;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.5	.;.;D;D;D;.;.;.
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	.;.;D;D;D;.;.;.
Sift4G	Uncertain	0.0040	D;D;D;D;D;.;.;D
Vest4		0.93, 0.91
MVP		0.95
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.21
gMVP		0.71

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-26921185;