19-7645154-T-C

Variant names:

• chr19-7645154-T-C
• rs929807
• NM_006949.4:c.1247-43T>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.1247-43T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.394 in 1,543,710 control chromosomes in the GnomAD database, including 125,034 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.46 (16859 hom., cov: 33)
  • Exomes 𝑓: 0.39 (108175 hom.)
• Consequence: STXBP2 NM_006949.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.54
• Publications: 13 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: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 2 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 19-7645154-T-C is Benign according to our data. Variant chr19-7645154-T-C is described in ClinVar as Benign. ClinVar VariationId is 260087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.684 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STXBP2	NM_006949.4	c.1247-43T>C		intron_variant	Intron 14 of 18	ENST00000221283.10	NP_008880.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STXBP2	ENST00000221283.10	c.1247-43T>C		intron_variant	Intron 14 of 18	1	NM_006949.4	ENSP00000221283.4
ENSG00000268400	ENST00000698368.1	n.*1350-43T>C		intron_variant	Intron 16 of 19			ENSP00000513686.1

Frequencies

GnomAD3 genomes AF: 0.458 AC: 69598 AN: 151950 Hom.: 16824 Cov.: 33

Gnomad AFR AF: 0.584

Gnomad AMI AF: 0.208

Gnomad AMR AF: 0.473

Gnomad ASJ AF: 0.311

Gnomad EAS AF: 0.704

Gnomad SAS AF: 0.362

Gnomad FIN AF: 0.527

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.367

Gnomad OTH AF: 0.435

GnomAD2 exomes AF: 0.424 AC: 65453 AN: 154326 AF XY: 0.415

Gnomad AFR exome AF: 0.592

Gnomad AMR exome AF: 0.458

Gnomad ASJ exome AF: 0.303

Gnomad EAS exome AF: 0.677

Gnomad FIN exome AF: 0.509

Gnomad NFE exome AF: 0.366

Gnomad OTH exome AF: 0.401

GnomAD4 exome AF: 0.387 AC: 538061 AN: 1391642 Hom.: 108175 Cov.: 29 AF XY: 0.385 AC XY: 264268 AN XY: 686858

African (AFR) AF: 0.598 AC: 18805 AN: 31452

American (AMR) AF: 0.462 AC: 16502 AN: 35694

Ashkenazi Jewish (ASJ) AF: 0.307 AC: 7714 AN: 25146

East Asian (EAS) AF: 0.724 AC: 25833 AN: 35702

South Asian (SAS) AF: 0.343 AC: 27117 AN: 79036

European-Finnish (FIN) AF: 0.502 AC: 24652 AN: 49098

Middle Eastern (MID) AF: 0.334 AC: 1878 AN: 5626

European-Non Finnish (NFE) AF: 0.366 AC: 392302 AN: 1072166

Other (OTH) AF: 0.403 AC: 23258 AN: 57722

GnomAD4 genome AF: 0.458 AC: 69690 AN: 152068 Hom.: 16859 Cov.: 33 AF XY: 0.464 AC XY: 34492 AN XY: 74342

African (AFR) AF: 0.584 AC: 24228 AN: 41466

American (AMR) AF: 0.473 AC: 7234 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.311 AC: 1079 AN: 3470

East Asian (EAS) AF: 0.703 AC: 3630 AN: 5162

South Asian (SAS) AF: 0.362 AC: 1747 AN: 4828

European-Finnish (FIN) AF: 0.527 AC: 5588 AN: 10596

Middle Eastern (MID) AF: 0.361 AC: 106 AN: 294

European-Non Finnish (NFE) AF: 0.367 AC: 24960 AN: 67938

Other (OTH) AF: 0.439 AC: 928 AN: 2114

Alfa AF: 0.395 Hom.: 2264

Bravo AF: 0.461

Asia WGS AF: 0.533 AC: 1854 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 71% of patients studied by a panel of primary immunodeficiencies. Number of patients: 68. Only high quality variants are reported. -

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	-0.92
CADD	Benign	0.43
DANN	Benign	0.24
PhyloP100		-1.5
BranchPoint Hunter		2.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs929807; hg19: chr19-7710040;