rs61407177

Positions:

• chr19-7645187-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000221283.10(STXBP2):​c.1247-10C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0129 in 1,555,264 control chromosomes in the GnomAD database, including 939 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (262 hom., cov: 34)
  • Exomes 𝑓: 0.010 (677 hom.)
• Consequence: STXBP2 ENST00000221283.10 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001560
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.77

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 19-7645187-C-T is Benign according to our data. Variant chr19-7645187-C-T is described in ClinVar as [Benign]. Clinvar id is 260086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.115 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STXBP2	NM_006949.4	c.1247-10C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000221283.10	NP_008880.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STXBP2	ENST00000221283.10	c.1247-10C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_006949.4	ENSP00000221283	P4

Frequencies

GnomAD3 genomes AF: 0.0392 AC: 5968 AN: 152196 Hom.: 257 Cov.: 34

Gnomad AFR AF: 0.0756

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.120

Gnomad ASJ AF: 0.0285

Gnomad EAS AF: 0.0300

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.0471

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00215

Gnomad OTH AF: 0.0377

GnomAD3 exomes AF: 0.0394 AC: 6406 AN: 162392 Hom.: 421 AF XY: 0.0321 AC XY: 2755 AN XY: 85918

Gnomad AFR exome AF: 0.0804

Gnomad AMR exome AF: 0.164

Gnomad ASJ exome AF: 0.0278

Gnomad EAS exome AF: 0.0288

Gnomad SAS exome AF: 0.00138

Gnomad FIN exome AF: 0.0402

Gnomad NFE exome AF: 0.00193

Gnomad OTH exome AF: 0.0320

GnomAD4 exome AF: 0.00998 AC: 14000 AN: 1402950 Hom.: 677 Cov.: 33 AF XY: 0.00910 AC XY: 6299 AN XY: 692406

Gnomad4 AFR exome AF: 0.0791

Gnomad4 AMR exome AF: 0.158

Gnomad4 ASJ exome AF: 0.0278

Gnomad4 EAS exome AF: 0.0271

Gnomad4 SAS exome AF: 0.00171

Gnomad4 FIN exome AF: 0.0382

Gnomad4 NFE exome AF: 0.000857

Gnomad4 OTH exome AF: 0.0185

GnomAD4 genome AF: 0.0393 AC: 5992 AN: 152314 Hom.: 262 Cov.: 34 AF XY: 0.0416 AC XY: 3102 AN XY: 74484

Gnomad4 AFR AF: 0.0759

Gnomad4 AMR AF: 0.120

Gnomad4 ASJ AF: 0.0285

Gnomad4 EAS AF: 0.0297

Gnomad4 SAS AF: 0.00352

Gnomad4 FIN AF: 0.0471

Gnomad4 NFE AF: 0.00215

Gnomad4 OTH AF: 0.0373

Alfa AF: 0.0231 Hom.: 38

Bravo AF: 0.0466

Asia WGS AF: 0.0360 AC: 123 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 26% of patients studied by a panel of primary immunodeficiencies. Number of patients: 25. Only high quality variants are reported. -

Familial hemophagocytic lymphohistiocytosis 5 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.93
DANN	Benign	0.45

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000016
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

Publications

LitVar

Other links and lift over

dbSNP: rs61407177; hg19: chr19-7710073;