rs151257815

chr19-7642425-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006949.4(STXBP2):c.795-4C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0174 in 1,613,936 control chromosomes in the GnomAD database, including 310 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (16 hom., cov: 32)
  • Exomes 𝑓: 0.018 (294 hom.)
• Consequence: STXBP2 NM_006949.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002348
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.551

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 19-7642425-C-T is Benign according to our data. Variant chr19-7642425-C-T is described in ClinVar as [Benign]. Clinvar id is 193692.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0115 (1753/152316) while in subpopulation NFE AF= 0.0199 (1355/68008). AF 95% confidence interval is 0.019. There are 16 homozygotes in gnomad4. There are 773 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STXBP2	NM_006949.4	c.795-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000221283.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STXBP2	ENST00000221283.10	c.795-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_006949.4	P4

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1753 AN: 152198 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00364

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00569

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0106

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0199

Gnomad OTH AF: 0.00908

GnomAD3 exomes AF: 0.0118 AC: 2958 AN: 251186 Hom.: 28 AF XY: 0.0119 AC XY: 1619 AN XY: 135816

Gnomad AFR exome AF: 0.00455

Gnomad AMR exome AF: 0.00353

Gnomad ASJ exome AF: 0.00437

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00408

Gnomad FIN exome AF: 0.0122

Gnomad NFE exome AF: 0.0199

Gnomad OTH exome AF: 0.0114

GnomAD4 exome AF: 0.0180 AC: 26344 AN: 1461620 Hom.: 294 Cov.: 35 AF XY: 0.0176 AC XY: 12804 AN XY: 727146

Gnomad4 AFR exome AF: 0.00308

Gnomad4 AMR exome AF: 0.00389

Gnomad4 ASJ exome AF: 0.00570

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00434

Gnomad4 FIN exome AF: 0.0121

Gnomad4 NFE exome AF: 0.0217

Gnomad4 OTH exome AF: 0.0127

GnomAD4 genome AF: 0.0115 AC: 1753 AN: 152316 Hom.: 16 Cov.: 32 AF XY: 0.0104 AC XY: 773 AN XY: 74476

Gnomad4 AFR AF: 0.00363

Gnomad4 AMR AF: 0.00568

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.0106

Gnomad4 NFE AF: 0.0199

Gnomad4 OTH AF: 0.00899

Alfa AF: 0.0153 Hom.: 9

Bravo AF: 0.0107

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0161

EpiControl AF: 0.0175

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 5 Benign:2

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 19, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

May 19, 2015

- -

STXBP2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 28, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2024

STXBP2: BP4, BS1, BS2 -

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.29
Dann	Benign	0.46

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000023
dbscSNV1_RF	Benign	0.0
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: rs151257815; hg19: chr19-7707311;