NM_006949.4:c.1356+18A>G

Variant names:

• chr19-7645324-A-G
• rs889187
• NM_006949.4:c.1356+18A>G

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.1356+18A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.391 in 1,563,216 control chromosomes in the GnomAD database, including 124,415 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (15738 hom., cov: 34)
  • Exomes 𝑓: 0.39 (108677 hom.)
• Consequence: STXBP2 NM_006949.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.379
• Publications: 14 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=-0.92).
• BP6: Variant 19-7645324-A-G is Benign according to our data. Variant chr19-7645324-A-G is described in ClinVar as Benign. ClinVar VariationId is 260088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.683 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STXBP2	NM_006949.4	c.1356+18A>G		intron_variant	Intron 15 of 18	ENST00000221283.10	NP_008880.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STXBP2	ENST00000221283.10	c.1356+18A>G		intron_variant	Intron 15 of 18	1	NM_006949.4	ENSP00000221283.4
ENSG00000268400	ENST00000698368.1	n.*1459+18A>G		intron_variant	Intron 17 of 19			ENSP00000513686.1

Frequencies

GnomAD3 genomes AF: 0.445 AC: 67619 AN: 152006 Hom.: 15704 Cov.: 34

Gnomad AFR AF: 0.538

Gnomad AMI AF: 0.209

Gnomad AMR AF: 0.470

Gnomad ASJ AF: 0.311

Gnomad EAS AF: 0.703

Gnomad SAS AF: 0.362

Gnomad FIN AF: 0.526

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.367

Gnomad OTH AF: 0.426

GnomAD2 exomes AF: 0.423 AC: 74270 AN: 175436 AF XY: 0.415

Gnomad AFR exome AF: 0.545

Gnomad AMR exome AF: 0.457

Gnomad ASJ exome AF: 0.304

Gnomad EAS exome AF: 0.678

Gnomad FIN exome AF: 0.511

Gnomad NFE exome AF: 0.368

Gnomad OTH exome AF: 0.400

GnomAD4 exome AF: 0.386 AC: 544019 AN: 1411092 Hom.: 108677 Cov.: 32 AF XY: 0.384 AC XY: 267644 AN XY: 697502

African (AFR) AF: 0.548 AC: 17653 AN: 32186

American (AMR) AF: 0.459 AC: 17345 AN: 37800

Ashkenazi Jewish (ASJ) AF: 0.307 AC: 7785 AN: 25360

East Asian (EAS) AF: 0.722 AC: 26712 AN: 37010

South Asian (SAS) AF: 0.343 AC: 27621 AN: 80558

European-Finnish (FIN) AF: 0.503 AC: 25085 AN: 49918

Middle Eastern (MID) AF: 0.333 AC: 1731 AN: 5196

European-Non Finnish (NFE) AF: 0.366 AC: 396711 AN: 1084702

Other (OTH) AF: 0.401 AC: 23376 AN: 58362

GnomAD4 genome AF: 0.445 AC: 67710 AN: 152124 Hom.: 15738 Cov.: 34 AF XY: 0.451 AC XY: 33564 AN XY: 74362

African (AFR) AF: 0.538 AC: 22345 AN: 41518

American (AMR) AF: 0.470 AC: 7182 AN: 15286

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

East Asian (EAS) AF: 0.703 AC: 3632 AN: 5170

South Asian (SAS) AF: 0.362 AC: 1744 AN: 4820

European-Finnish (FIN) AF: 0.526 AC: 5575 AN: 10592

Middle Eastern (MID) AF: 0.357 AC: 105 AN: 294

European-Non Finnish (NFE) AF: 0.367 AC: 24949 AN: 67950

Other (OTH) AF: 0.430 AC: 909 AN: 2114

Alfa AF: 0.394 Hom.: 2302

Bravo AF: 0.447

Asia WGS AF: 0.533 AC: 1851 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

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 70% of patients studied by a panel of primary immunodeficiencies. Number of patients: 67. Only high quality variants are reported. -

Mar 08, 2018

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial hemophagocytic lymphohistiocytosis 5 Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Nov 12, 2018

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.60
DANN	Benign	0.21
PhyloP100		-0.38
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs889187; hg19: chr19-7710210; COSMIC: COSV55405675; COSMIC: COSV55405675;