4-26957684-A-G

Position:

• chr4-26957684-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_020860.4(STIM2):​c.355A>G​(p.Ile119Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000277 in 1,445,462 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: STIM2 NM_020860.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.37

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STIM2	NM_020860.4	c.355A>G	p.Ile119Val	missense_variant	3/12	ENST00000467087.7	NP_065911.3
STIM2	NM_001169118.2	c.355A>G	p.Ile119Val	missense_variant	3/13		NP_001162589.1
STIM2	NM_001169117.2	c.355A>G	p.Ile119Val	missense_variant	3/13		NP_001162588.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STIM2	ENST00000467087.7	c.355A>G	p.Ile119Val	missense_variant	3/12	1	NM_020860.4	ENSP00000419073.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000277 AC: 4 AN: 1445462 Hom.: 0 Cov.: 29 AF XY: 0.00000417 AC XY: 3 AN XY: 718962

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000250

Gnomad4 ASJ exome AF: 0.0000390

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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

Jul 30, 2024

The c.355A>G (p.I119V) alteration is located in exon 3 (coding exon 3) of the STIM2 gene. This alteration results from a A to G substitution at nucleotide position 355, causing the isoleucine (I) at amino acid position 119 to be replaced by a valine (V). 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	0.45
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	.;.;.;T;T;T;.;T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.71	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Uncertain	2.2	.;.;.;.;.;M;.;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.92	.;.;N;N;N;.;.;.
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	.;.;D;D;D;.;.;.
Sift4G	Uncertain	0.013	D;D;D;D;D;.;.;D
Vest4		0.60
MVP		0.58
ClinPred		0.89	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.40

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: rs1277356845; hg19: chr4-26959306;