chr4-26861364-T-A

Position:

• chr4-26861364-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020860.4(STIM2):​c.146T>A​(p.Met49Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000255 in 1,176,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000026 (0 hom.)
• Consequence: STIM2 NM_020860.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.851

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14340359).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STIM2	NM_020860.4	c.146T>A	p.Met49Lys	missense_variant	1/12	ENST00000467087.7	NP_065911.3
STIM2	NM_001169118.2	c.146T>A	p.Met49Lys	missense_variant	1/13		NP_001162589.1
STIM2	NM_001169117.2	c.146T>A	p.Met49Lys	missense_variant	1/13		NP_001162588.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STIM2	ENST00000467087.7	c.146T>A	p.Met49Lys	missense_variant	1/12	1	NM_020860.4	ENSP00000419073.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000255 AC: 3 AN: 1176184 Hom.: 0 Cov.: 31 AF XY: 0.00000175 AC XY: 1 AN XY: 571990

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000748

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000210

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

May 31, 2023

The c.146T>A (p.M49K) alteration is located in exon 1 (coding exon 1) of the STIM2 gene. This alteration results from a T to A substitution at nucleotide position 146, causing the methionine (M) at amino acid position 49 to be replaced by a lysine (K). 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	0.080
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	18
DANN	Benign	0.79
DEOGEN2	Benign	0.036	.;T;T;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.58	T;T;T;T;T
M_CAP	Pathogenic	0.87	D
MetaRNN	Benign	0.14	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.34	.;.;.;N;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.070	N;N;N;.;.
REVEL	Benign	0.24
Sift	Benign	0.22	T;T;T;.;.
Sift4G	Uncertain	0.030	D;D;D;.;.
Vest4		0.30
MVP		0.39
ClinPred		0.095	T
GERP RS		1.9
Varity_R		0.32
gMVP		0.32

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: rs1722180014; hg19: chr4-26862986;