chr19-7642425-C-T

Variant names:

• chr19-7642425-C-T
• rs151257815
• NM_006949.4:c.795-4C>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.795-4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0174 in 1,613,936 control chromosomes in the GnomAD database, including 310 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (16 hom., cov: 32)
  • Exomes 𝑓: 0.018 (294 hom.)
• Consequence: STXBP2 NM_006949.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002348
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.551
• Publications: 11 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: AD, AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, ClinGen, PanelApp Australia, 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 19-7642425-C-T is Benign according to our data. Variant chr19-7642425-C-T is described in ClinVar as Benign. ClinVar VariationId is 193692.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0115 (1753/152316) while in subpopulation NFE AF = 0.0199 (1355/68008). AF 95% confidence interval is 0.019. There are 16 homozygotes in GnomAd4. There are 773 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 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.795-4C>T		splice_region intron	N/A	NP_008880.2	Q15833-1
	STXBP2	NM_001272034.2		c.828-4C>T		splice_region intron	N/A	NP_001258963.1	Q15833-3
	STXBP2	NM_001127396.3		c.786-4C>T		splice_region intron	N/A	NP_001120868.1	Q15833-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STXBP2	ENST00000221283.10	TSL:1 MANE Select	c.795-4C>T		splice_region intron	N/A	ENSP00000221283.4	Q15833-1
	STXBP2	ENST00000414284.6	TSL:1	c.786-4C>T		splice_region intron	N/A	ENSP00000409471.1	Q15833-2
	STXBP2	ENST00000597068.5	TSL:1	n.795-4C>T		splice_region intron	N/A	ENSP00000471327.1	M0R0M7

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1753 AN: 152198 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00364

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00569

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0106

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0199

Gnomad OTH AF: 0.00908

GnomAD2 exomes AF: 0.0118 AC: 2958 AN: 251186 AF XY: 0.0119

Gnomad AFR exome AF: 0.00455

Gnomad AMR exome AF: 0.00353

Gnomad ASJ exome AF: 0.00437

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0122

Gnomad NFE exome AF: 0.0199

Gnomad OTH exome AF: 0.0114

GnomAD4 exome AF: 0.0180 AC: 26344 AN: 1461620 Hom.: 294 Cov.: 35 AF XY: 0.0176 AC XY: 12804 AN XY: 727146

African (AFR) AF: 0.00308 AC: 103 AN: 33478

American (AMR) AF: 0.00389 AC: 174 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00570 AC: 149 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00434 AC: 374 AN: 86256

European-Finnish (FIN) AF: 0.0121 AC: 646 AN: 53182

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.0217 AC: 24122 AN: 1111982

Other (OTH) AF: 0.0127 AC: 768 AN: 60394

GnomAD4 genome AF: 0.0115 AC: 1753 AN: 152316 Hom.: 16 Cov.: 32 AF XY: 0.0104 AC XY: 773 AN XY: 74476

African (AFR) AF: 0.00363 AC: 151 AN: 41574

American (AMR) AF: 0.00568 AC: 87 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4828

European-Finnish (FIN) AF: 0.0106 AC: 113 AN: 10630

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

European-Non Finnish (NFE) AF: 0.0199 AC: 1355 AN: 68008

Other (OTH) AF: 0.00899 AC: 19 AN: 2114

Alfa AF: 0.0153 Hom.: 9

Bravo AF: 0.0107

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0161

EpiControl AF: 0.0175

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Familial hemophagocytic lymphohistiocytosis 5 (2)
-	-	1	Autoinflammatory syndrome (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	STXBP2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.29
DANN	Benign	0.46
PhyloP100		-0.55
PromoterAI		0.025	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000023
dbscSNV1_RF	Benign	0.0
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: rs151257815; hg19: chr19-7707311;