19-7639112-C-T

Variant names:

• chr19-7639112-C-T
• rs115239774
• NM_006949.4:c.169+12C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006949.4(STXBP2):​c.169+12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00193 in 1,613,868 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0093 (23 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (21 hom.)
• Consequence: STXBP2 NM_006949.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.174
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 19-7639112-C-T is Benign according to our data. Variant chr19-7639112-C-T is described in ClinVar as Benign. ClinVar VariationId is 260098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00934 (1423/152318) while in subpopulation AFR AF = 0.0311 (1294/41558). AF 95% confidence interval is 0.0297. There are 23 homozygotes in GnomAd4. There are 689 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 23 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006949.4. 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.169+12C>T		intron	N/A	NP_008880.2
	STXBP2	NM_001272034.2		c.169+12C>T		intron	N/A	NP_001258963.1
	STXBP2	NM_001127396.3		c.169+12C>T		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.169+12C>T		intron	N/A	ENSP00000221283.4
	STXBP2	ENST00000414284.6	TSL:1	c.169+12C>T		intron	N/A	ENSP00000409471.1
	STXBP2	ENST00000597068.5	TSL:1	n.169+12C>T		intron	N/A	ENSP00000471327.1

Frequencies

GnomAD3 genomes AF: 0.00934 AC: 1421 AN: 152200 Hom.: 23 Cov.: 33

Gnomad AFR AF: 0.0312

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00307

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00886

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.00311 AC: 776 AN: 249568 AF XY: 0.00240

Gnomad AFR exome AF: 0.0329

Gnomad AMR exome AF: 0.00154

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00817

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000107

Gnomad OTH exome AF: 0.00213

GnomAD4 exome AF: 0.00116 AC: 1691 AN: 1461550 Hom.: 21 Cov.: 32 AF XY: 0.00103 AC XY: 746 AN XY: 727082

African (AFR) AF: 0.0330 AC: 1104 AN: 33470

American (AMR) AF: 0.00181 AC: 81 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26128

East Asian (EAS) AF: 0.00529 AC: 210 AN: 39696

South Asian (SAS) AF: 0.000557 AC: 48 AN: 86214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00399 AC: 23 AN: 5768

European-Non Finnish (NFE) AF: 0.0000594 AC: 66 AN: 1111826

Other (OTH) AF: 0.00262 AC: 158 AN: 60384

GnomAD4 genome AF: 0.00934 AC: 1423 AN: 152318 Hom.: 23 Cov.: 33 AF XY: 0.00925 AC XY: 689 AN XY: 74480

African (AFR) AF: 0.0311 AC: 1294 AN: 41558

American (AMR) AF: 0.00307 AC: 47 AN: 15310

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

East Asian (EAS) AF: 0.00888 AC: 46 AN: 5180

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68026

Other (OTH) AF: 0.00851 AC: 18 AN: 2114

Alfa AF: 0.00140 Hom.: 1

Bravo AF: 0.0100

Asia WGS AF: 0.0120 AC: 42 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Familial hemophagocytic lymphohistiocytosis 5 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.3
DANN	Benign	0.30
PhyloP100		-0.17
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)		0.030		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: rs115239774; hg19: chr19-7703998;