rs116022728

Variant names:

• chr19-7643083-G-A
• rs116022728
• NM_006949.4:c.1026+35G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001272034.2(STXBP2):​c.1059+35G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00236 in 1,614,008 control chromosomes in the GnomAD database, including 76 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (36 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (40 hom.)
• Consequence: STXBP2 NM_001272034.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.394
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 19-7643083-G-A is Benign according to our data. Variant chr19-7643083-G-A is described in ClinVar as Benign. ClinVar VariationId is 260082.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0122 (1856/152290) while in subpopulation AFR AF = 0.0415 (1724/41540). AF 95% confidence interval is 0.0399. There are 36 homozygotes in GnomAd4. There are 871 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 36 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001272034.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STXBP2	NM_006949.4	MANE Select	c.1026+35G>A		intron	N/A	NP_008880.2
	STXBP2	NM_001272034.2		c.1059+35G>A		intron	N/A	NP_001258963.1
	STXBP2	NM_001127396.3		c.1017+35G>A		intron	N/A	NP_001120868.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STXBP2	ENST00000221283.10	TSL:1 MANE Select	c.1026+35G>A		intron	N/A	ENSP00000221283.4
	STXBP2	ENST00000414284.6	TSL:1	c.1017+35G>A		intron	N/A	ENSP00000409471.1
	STXBP2	ENST00000597068.5	TSL:1	n.1026+35G>A		intron	N/A	ENSP00000471327.1

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1851 AN: 152172 Hom.: 36 Cov.: 32

Gnomad AFR AF: 0.0415

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00596

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00325 AC: 818 AN: 251316 AF XY: 0.00230

Gnomad AFR exome AF: 0.0431

Gnomad AMR exome AF: 0.00188

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00133 AC: 1949 AN: 1461718 Hom.: 40 Cov.: 35 AF XY: 0.00114 AC XY: 828 AN XY: 727154

African (AFR) AF: 0.0434 AC: 1453 AN: 33476

American (AMR) AF: 0.00233 AC: 104 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

Middle Eastern (MID) AF: 0.00867 AC: 50 AN: 5768

European-Non Finnish (NFE) AF: 0.0000881 AC: 98 AN: 1111906

Other (OTH) AF: 0.00358 AC: 216 AN: 60390

GnomAD4 genome AF: 0.0122 AC: 1856 AN: 152290 Hom.: 36 Cov.: 32 AF XY: 0.0117 AC XY: 871 AN XY: 74470

African (AFR) AF: 0.0415 AC: 1724 AN: 41540

American (AMR) AF: 0.00595 AC: 91 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68024

Other (OTH) AF: 0.0114 AC: 24 AN: 2114

Alfa AF: 0.00688 Hom.: 2

Bravo AF: 0.0145

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.54
DANN	Benign	0.76
PhyloP100		-0.39
PromoterAI		0.0038	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs116022728; hg19: chr19-7707969;