19-7645248-C-T

Variant summary

Our verdict is Benign. The variant received -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. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A433A) has been classified 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

1
17

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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 34. This position FAILED quality control check.
BS2
High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
STXBP2NM_006949.4 linkc.1298C>T p.Ala433Val missense_variant Exon 15 of 19 ENST00000221283.10 NP_008880.2 Q15833-1Q53GF4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
STXBP2ENST00000221283.10 linkc.1298C>T p.Ala433Val missense_variant Exon 15 of 19 1 NM_006949.4 ENSP00000221283.4 Q15833-1
ENSG00000268400ENST00000698368.1 linkn.*1401C>T non_coding_transcript_exon_variant Exon 17 of 20 ENSP00000513686.1 A0A8V8TM65
ENSG00000268400ENST00000698368.1 linkn.*1401C>T 3_prime_UTR_variant Exon 17 of 20 ENSP00000513686.1 A0A8V8TM65

Frequencies

GnomAD3 genomes
AF:
0.00866
AC:
1318
AN:
152242
Hom.:
4
Cov.:
34
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
GnomAD2 exomes
AF:
0.00826
AC:
1662
AN:
201122
AF XY:
0.00839
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 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.:
34
AF XY:
0.0113
AC XY:
8008
AN XY:
708292
show subpopulations
Gnomad4 AFR exome
AF:
0.00165
AC:
54
AN:
32804
Gnomad4 AMR exome
AF:
0.00988
AC:
402
AN:
40708
Gnomad4 ASJ exome
AF:
0.00407
AC:
104
AN:
25522
Gnomad4 EAS exome
AF:
0.0000262
AC:
1
AN:
38180
Gnomad4 SAS exome
AF:
0.00620
AC:
509
AN:
82054
Gnomad4 FIN exome
AF:
0.00325
AC:
165
AN:
50750
Gnomad4 NFE exome
AF:
0.0129
AC:
14168
AN:
1095198
Gnomad4 Remaining exome
AF:
0.0103
AC:
607
AN:
59130
Heterozygous variant carriers
0
916
1833
2749
3666
4582
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Exome Hom
Variant carriers
0
544
1088
1632
2176
2720
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00866
AC:
1319
AN:
152360
Hom.:
4
Cov.:
34
AF XY:
0.00816
AC XY:
608
AN XY:
74512
show subpopulations
Gnomad4 AFR
AF:
0.00207
AC:
0.002068
AN:
0.002068
Gnomad4 AMR
AF:
0.0152
AC:
0.0151575
AN:
0.0151575
Gnomad4 ASJ
AF:
0.00518
AC:
0.00518433
AN:
0.00518433
Gnomad4 EAS
AF:
0.00
AC:
0
AN:
0
Gnomad4 SAS
AF:
0.00373
AC:
0.00372517
AN:
0.00372517
Gnomad4 FIN
AF:
0.00329
AC:
0.00329195
AN:
0.00329195
Gnomad4 NFE
AF:
0.0128
AC:
0.0128341
AN:
0.0128341
Gnomad4 OTH
AF:
0.0151
AC:
0.0151229
AN:
0.0151229
Heterozygous variant carriers
0
73
146
218
291
364
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Genome Het
Genome Hom
Variant carriers
0
20
40
60
80
100
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0106
Hom.:
36
Bravo
AF:
0.00876
TwinsUK
AF:
0.0121
AC:
45
ALSPAC
AF:
0.0114
AC:
44
ESP6500AA
AF:
0.00137
AC:
6
ESP6500EA
AF:
0.0121
AC:
104
ExAC
AF:
0.00621
AC:
747
Asia WGS
AF:
0.00202
AC:
7
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
Feb 14, 2017
Genetic Services Laboratory, University of Chicago
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

May 05, 2015
Eurofins Ntd Llc (ga)
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Mar 29, 2016
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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 -

-
PreventionGenetics, part of Exact Sciences
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Familial hemophagocytic lymphohistiocytosis 5 Benign:2
May 28, 2019
Mendelics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Benign:2
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Nov 01, 2022
CeGaT Center for Human Genetics Tuebingen
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

STXBP2: BP4, BS1, BS2 -

Autoinflammatory syndrome Benign:1
Apr 04, 2022
Genome Diagnostics Laboratory, The Hospital for Sick Children
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
Benign
0.097
BayesDel_addAF
Benign
-0.47
T
BayesDel_noAF
Benign
-0.44
CADD
Benign
22
DANN
Benign
0.91
DEOGEN2
Benign
0.15
.;T;.
Eigen
Benign
-0.79
Eigen_PC
Benign
-0.74
FATHMM_MKL
Benign
0.37
N
LIST_S2
Uncertain
0.88
D;D;D
MetaRNN
Benign
0.0038
T;T;T
MetaSVM
Benign
-0.91
T
MutationAssessor
Benign
0.86
.;L;.
PrimateAI
Benign
0.46
T
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
T
GERP RS
3.0
Varity_R
0.13
gMVP
0.37
Mutation Taster
=85/15
polymorphism

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.

Other links and lift over

dbSNP: rs141309384; hg19: chr19-7710134; COSMIC: COSV99066080; COSMIC: COSV99066080; API