rs201649843

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6

The NM_006949.4(STXBP2):c.661G>A(p.Glu221Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000168 in 1,614,096 control chromosomes in the GnomAD database, including 1 homozygotes. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 1 hom. )

Consequence

STXBP2
NM_006949.4 missense, splice_region

Scores

Splicing: ADA: 0.6049

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 6.46

Variant links:

Genes affected

STXBP2 (HGNC:11445): (syntaxin binding protein 2) This gene encodes a member of the STXBP/unc-18/SEC1 family. The encoded protein is involved in intracellular trafficking, control of SNARE (soluble NSF attachment protein receptor) complex assembly, and the release of cytotoxic granules by natural killer cells. Mutations in this gene are associated with familial hemophagocytic lymphohistiocytosis. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Jan 2013]

STXBP2 links:

ENSG00000268400 (HGNC:):

ENSG00000268400 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP6

Variant 19-7642116-G-A is Benign according to our data. Variant chr19-7642116-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 567849.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STXBP2	NM_006949.4 link	c.661G>A	p.Glu221Lys	missense_variant, splice_region_variant	Exon 8 of 19	ENST00000221283.10	NP_008880.2	Q15833-1Q53GF4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
STXBP2	ENST00000221283.10 link	c.661G>A	p.Glu221Lys	missense_variant, splice_region_variant	Exon 8 of 19	1	NM_006949.4	ENSP00000221283.4	Q15833-1
ENSG00000268400	ENST00000698368.1 link	n.*764G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 10 of 20			ENSP00000513686.1	A0A8V8TM65
ENSG00000268400	ENST00000698368.1 link	n.*764G>A		3_prime_UTR_variant	Exon 10 of 20			ENSP00000513686.1	A0A8V8TM65

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.000139

AC:

AN:

250952

Hom.:

AF XY:

0.000147

AC XY:

AN XY:

135764

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000521

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:

0.000141

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000172

AC:

252

AN:

1461824

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

117

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000425

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000198

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000125

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.000240

Hom.:

Bravo

AF:

0.000159

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Aug 29, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.661G>A (p.E221K) alteration is located in exon 8 (coding exon 8) of the STXBP2 gene. This alteration results from a G to A substitution at nucleotide position 661, causing the glutamic acid (E) at amino acid position 221 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Apr 04, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Familial hemophagocytic lymphohistiocytosis 5

Benign:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.064

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.41

.;.;T;.

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.94

D;D;D;D

M_CAP

Uncertain

0.13

MetaRNN

Uncertain

0.58

D;T;T;T

MetaSVM

Uncertain

0.0065

MutationAssessor

Benign

2.0

.;.;M;.

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-2.8

.;D;D;D

REVEL

Uncertain

0.61

Sift

Benign

0.24

.;T;T;T

Sift4G

Uncertain

0.0050

D;T;T;T

Polyphen

1.0

.;.;D;D

Vest4

0.78, 0.78, 0.79

MVP

0.86

MPC

0.84

ClinPred

0.48

GERP RS

4.4

Varity_R

0.67

gMVP

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.60

dbscSNV1_RF

Pathogenic

0.77

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