19-7645248-C-T

Position:

chr19-7645248-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006949.4(STXBP2):c.1298C>T(p.Ala433Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.011 in 1,582,430 control chromosomes in the GnomAD database, including 129 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0087 ( 4 hom., cov: 34)

Exomes 𝑓: 0.011 ( 125 hom. )

Consequence

STXBP2
NM_006949.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.06

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003764242).

BP6

Variant 19-7645248-C-T is Benign according to our data. Variant chr19-7645248-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 194525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-7645248-C-T is described in Lovd as [Benign]. Variant chr19-7645248-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00866 (1319/152360) while in subpopulation AMR AF= 0.0152 (232/15306). AF 95% confidence interval is 0.0136. There are 4 homozygotes in gnomad4. There are 608 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STXBP2	NM_006949.4 linkuse as main transcript	c.1298C>T	p.Ala433Val	missense_variant	15/19	ENST00000221283.10	NP_008880.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STXBP2	ENST00000221283.10 linkuse as main transcript	c.1298C>T	p.Ala433Val	missense_variant	15/19	1	NM_006949.4	ENSP00000221283	P4	Q15833-1

Frequencies

GnomAD3 genomes

AF:

0.00866

AC:

1318

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00207

Gnomad AMI

AF:

0.0241

Gnomad AMR

AF:

0.0152

Gnomad ASJ

AF:

0.00518

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00372

Gnomad FIN

AF:

0.00329

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0128

Gnomad OTH

AF:

0.0153

GnomAD3 exomes

AF:

0.00826

AC:

1662

AN:

201122

Hom.:

AF XY:

0.00839

AC XY:

907

AN XY:

108130

show subpopulations

Gnomad AFR exome

AF:

0.00136

Gnomad AMR exome

AF:

0.00956

Gnomad ASJ exome

AF:

0.00372

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00592

Gnomad FIN exome

AF:

0.00207

Gnomad NFE exome

AF:

0.0124

Gnomad OTH exome

AF:

0.0130

GnomAD4 exome

AF:

0.0113

AC:

16143

AN:

1430070

Hom.:

125

Cov.:

AF XY:

0.0113

AC XY:

8008

AN XY:

708292

show subpopulations

Gnomad4 AFR exome

AF:

0.00165

Gnomad4 AMR exome

AF:

0.00988

Gnomad4 ASJ exome

AF:

0.00407

Gnomad4 EAS exome

AF:

0.0000262

Gnomad4 SAS exome

AF:

0.00620

Gnomad4 FIN exome

AF:

0.00325

Gnomad4 NFE exome

AF:

0.0129

Gnomad4 OTH exome

AF:

0.0103

GnomAD4 genome

AF:

0.00866

AC:

1319

AN:

152360

Hom.:

Cov.:

AF XY:

0.00816

AC XY:

608

AN XY:

74512

show subpopulations

Gnomad4 AFR

AF:

0.00207

Gnomad4 AMR

AF:

0.0152

Gnomad4 ASJ

AF:

0.00518

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00373

Gnomad4 FIN

AF:

0.00329

Gnomad4 NFE

AF:

0.0128

Gnomad4 OTH

AF:

0.0151

Alfa

AF:

0.0101

Hom.:

Bravo

AF:

0.00876

TwinsUK

AF:

0.0121

AC:

ALSPAC

AF:

0.0114

AC:

ESP6500AA

AF:

0.00137

AC:

ESP6500EA

AF:

0.0121

AC:

104

ExAC

AF:

0.00621

AC:

747

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 1.6% of total chromosomes in ExAC, 2.7% (44/1612) of Latino chromosomes -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 05, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 14, 2017	- -

Familial hemophagocytic lymphohistiocytosis 5

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	STXBP2: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autoinflammatory syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.15

.;T;.

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.37

LIST_S2

Uncertain

0.88

D;D;D

MetaRNN

Benign

0.0038

T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.86

.;L;.

MutationTaster

Benign

0.95

N;N;N

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.4

N;N;N

REVEL

Benign

0.12

Sift

Benign

0.31

T;T;T

Sift4G

Benign

0.31

T;T;T

Polyphen

0.037, 0.030

.;B;B

Vest4

0.22

MVP

0.64

MPC

0.24

ClinPred

0.0019

GERP RS

3.0

Varity_R

0.13

gMVP

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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