chr19-7647539-G-C

Variant names:

• chr19-7647539-G-C
• rs34976997
• NM_006949.4:c.1696+28G>C

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.1696+28G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.348 in 1,573,874 control chromosomes in the GnomAD database, including 96,029 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (9250 hom., cov: 31)
  • Exomes 𝑓: 0.35 (86779 hom.)
• Consequence: STXBP2 NM_006949.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.63
• Publications: 10 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=-0.8).
• BP6: Variant 19-7647539-G-C is Benign according to our data. Variant chr19-7647539-G-C is described in CliVar as Benign. Clinvar id is 260100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-7647539-G-C is described in CliVar as Benign. Clinvar id is 260100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-7647539-G-C is described in CliVar as Benign. Clinvar id is 260100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-7647539-G-C is described in CliVar as Benign. Clinvar id is 260100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-7647539-G-C is described in CliVar as Benign. Clinvar id is 260100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-7647539-G-C is described in CliVar as Benign. Clinvar id is 260100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-7647539-G-C is described in CliVar as Benign. Clinvar id is 260100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-7647539-G-C is described in CliVar as Benign. Clinvar id is 260100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-7647539-G-C is described in CliVar as Benign. Clinvar id is 260100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.356 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STXBP2	NM_006949.4	c.1696+28G>C		intron_variant	Intron 18 of 18	ENST00000221283.10	NP_008880.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STXBP2	ENST00000221283.10	c.1696+28G>C		intron_variant	Intron 18 of 18	1	NM_006949.4	ENSP00000221283.4
ENSG00000268400	ENST00000698368.1	n.*1827G>C		downstream_gene_variant				ENSP00000513686.1

Frequencies

GnomAD3 genomes AF: 0.346 AC: 52567 AN: 151830 Hom.: 9232 Cov.: 31

Gnomad AFR AF: 0.330

Gnomad AMI AF: 0.207

Gnomad AMR AF: 0.364

Gnomad ASJ AF: 0.274

Gnomad EAS AF: 0.230

Gnomad SAS AF: 0.269

Gnomad FIN AF: 0.454

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.355

Gnomad OTH AF: 0.351

GnomAD2 exomes AF: 0.336 AC: 64667 AN: 192400 AF XY: 0.332

Gnomad AFR exome AF: 0.335

Gnomad AMR exome AF: 0.354

Gnomad ASJ exome AF: 0.269

Gnomad EAS exome AF: 0.212

Gnomad FIN exome AF: 0.444

Gnomad NFE exome AF: 0.355

Gnomad OTH exome AF: 0.355

GnomAD4 exome AF: 0.348 AC: 494449 AN: 1421926 Hom.: 86779 Cov.: 50 AF XY: 0.345 AC XY: 243285 AN XY: 704192

African (AFR) AF: 0.334 AC: 10697 AN: 32074

American (AMR) AF: 0.354 AC: 13695 AN: 38664

Ashkenazi Jewish (ASJ) AF: 0.273 AC: 6908 AN: 25272

East Asian (EAS) AF: 0.237 AC: 8787 AN: 37018

South Asian (SAS) AF: 0.271 AC: 22488 AN: 83078

European-Finnish (FIN) AF: 0.438 AC: 22327 AN: 51002

Middle Eastern (MID) AF: 0.309 AC: 1703 AN: 5520

European-Non Finnish (NFE) AF: 0.356 AC: 387985 AN: 1090582

Other (OTH) AF: 0.338 AC: 19859 AN: 58716

GnomAD4 genome AF: 0.346 AC: 52615 AN: 151948 Hom.: 9250 Cov.: 31 AF XY: 0.348 AC XY: 25833 AN XY: 74266

African (AFR) AF: 0.330 AC: 13677 AN: 41446

American (AMR) AF: 0.364 AC: 5557 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.274 AC: 951 AN: 3468

East Asian (EAS) AF: 0.230 AC: 1183 AN: 5140

South Asian (SAS) AF: 0.269 AC: 1292 AN: 4810

European-Finnish (FIN) AF: 0.454 AC: 4801 AN: 10570

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.355 AC: 24125 AN: 67918

Other (OTH) AF: 0.355 AC: 751 AN: 2114

Alfa AF: 0.235 Hom.: 776

Bravo AF: 0.339

Asia WGS AF: 0.282 AC: 983 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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 48% of patients studied by a panel of primary immunodeficiencies. Number of patients: 46. Only high quality variants are reported. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Familial hemophagocytic lymphohistiocytosis 5 Benign:1

Jul 15, 2021

Genome-Nilou Lab

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	-0.80
CADD	Benign	9.4
DANN	Benign	0.78
PhyloP100		2.6
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs34976997; hg19: chr19-7712425; COSMIC: COSV55405238; COSMIC: COSV55405238;