rs8104339

Variant names:

• chr19-7638719-C-T
• rs8104339
• NM_006949.4:c.38-7C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006949.4(STXBP2):​c.38-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.395 in 1,613,500 control chromosomes in the GnomAD database, including 129,930 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 0.43 (14545 hom., cov: 31)
  • Exomes 𝑓: 0.39 (115385 hom.)
• Consequence: STXBP2 NM_006949.4 splice_region, intron
• Scores: Splicing: ADA: 0.00009990
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 1.46
• Publications: 17 publications found

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 Gene-Disease associations (from GenCC):

• familial hemophagocytic lymphohistiocytosis 5

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• hereditary hemophagocytic lymphohistiocytosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• microvillus inclusion disease

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000268400 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 19-7638719-C-T is Benign according to our data. Variant chr19-7638719-C-T is described in ClinVar as Benign. ClinVar VariationId is 260104.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.652 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STXBP2	NM_006949.4	c.38-7C>T		splice_region_variant, intron_variant	Intron 1 of 18	ENST00000221283.10	NP_008880.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STXBP2	ENST00000221283.10	c.38-7C>T		splice_region_variant, intron_variant	Intron 1 of 18	1	NM_006949.4	ENSP00000221283.4
ENSG00000268400	ENST00000698368.1	n.*141-7C>T		splice_region_variant, intron_variant	Intron 3 of 19			ENSP00000513686.1

Frequencies

GnomAD3 genomes AF: 0.430 AC: 65227 AN: 151816 Hom.: 14524 Cov.: 31

Gnomad AFR AF: 0.508

Gnomad AMI AF: 0.246

Gnomad AMR AF: 0.370

Gnomad ASJ AF: 0.282

Gnomad EAS AF: 0.671

Gnomad SAS AF: 0.371

Gnomad FIN AF: 0.490

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.383

Gnomad OTH AF: 0.408

GnomAD2 exomes AF: 0.400 AC: 100573 AN: 251382 AF XY: 0.398

Gnomad AFR exome AF: 0.514

Gnomad AMR exome AF: 0.299

Gnomad ASJ exome AF: 0.277

Gnomad EAS exome AF: 0.654

Gnomad FIN exome AF: 0.483

Gnomad NFE exome AF: 0.381

Gnomad OTH exome AF: 0.391

GnomAD4 exome AF: 0.392 AC: 572736 AN: 1461566 Hom.: 115385 Cov.: 46 AF XY: 0.390 AC XY: 283881 AN XY: 727112

African (AFR) AF: 0.517 AC: 17305 AN: 33468

American (AMR) AF: 0.307 AC: 13742 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.280 AC: 7309 AN: 26134

East Asian (EAS) AF: 0.691 AC: 27449 AN: 39696

South Asian (SAS) AF: 0.353 AC: 30422 AN: 86254

European-Finnish (FIN) AF: 0.474 AC: 25317 AN: 53416

Middle Eastern (MID) AF: 0.335 AC: 1931 AN: 5764

European-Non Finnish (NFE) AF: 0.382 AC: 425217 AN: 1111732

Other (OTH) AF: 0.398 AC: 24044 AN: 60380

GnomAD4 genome AF: 0.430 AC: 65289 AN: 151934 Hom.: 14545 Cov.: 31 AF XY: 0.433 AC XY: 32164 AN XY: 74246

African (AFR) AF: 0.508 AC: 21016 AN: 41392

American (AMR) AF: 0.370 AC: 5653 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.282 AC: 980 AN: 3470

East Asian (EAS) AF: 0.670 AC: 3455 AN: 5154

South Asian (SAS) AF: 0.371 AC: 1786 AN: 4818

European-Finnish (FIN) AF: 0.490 AC: 5172 AN: 10562

Middle Eastern (MID) AF: 0.333 AC: 98 AN: 294

European-Non Finnish (NFE) AF: 0.383 AC: 26038 AN: 67940

Other (OTH) AF: 0.411 AC: 868 AN: 2110

Alfa AF: 0.391 Hom.: 9390

Bravo AF: 0.425

Asia WGS AF: 0.501 AC: 1741 AN: 3478

EpiCase AF: 0.385

EpiControl AF: 0.371

ClinVar

Significance: Benign

Submissions summary: Benign:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 51% of patients studied by a panel of primary immunodeficiencies. Number of patients: 49. Only high quality variants are reported. -

-

PreventionGenetics, part of Exact Sciences

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: 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: Frequency -

not provided Benign:2 Other:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Familial hemophagocytic lymphohistiocytosis 5 Benign:2

Jul 15, 2021

Genome-Nilou Lab

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

- -

Familial hemophagocytic lymphohistiocytosis Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	10
DANN	Benign	0.72
PhyloP100		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00010
dbscSNV1_RF	Benign	0.018
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

Other links and lift over

dbSNP: rs8104339; hg19: chr19-7703605;