rs61736589

Variant names:

• chr19-7647405-G-A
• rs61736589
• NM_006949.4:c.1590G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-7647405-G-A
• chr19-7647405-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006949.4(STXBP2):​c.1590G>A​(p.Ala530Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,613,456 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (16 hom., cov: 33)
  • Exomes 𝑓: 0.00090 (19 hom.)
• Consequence: STXBP2 NM_006949.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -5.95
• 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: 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 19-7647405-G-A is Benign according to our data. Variant chr19-7647405-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.95 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00844 (1285/152290) while in subpopulation AFR AF = 0.0295 (1225/41552). AF 95% confidence interval is 0.0281. There are 16 homozygotes in GnomAd4. There are 609 alleles in the male GnomAd4 subpopulation. Median coverage is 33. 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.1590G>A	p.Ala530Ala	synonymous	Exon 18 of 19	NP_008880.2	Q15833-1
	STXBP2	NM_001272034.2		c.1623G>A	p.Ala541Ala	synonymous	Exon 18 of 19	NP_001258963.1	Q15833-3
	STXBP2	NM_001127396.3		c.1581G>A	p.Ala527Ala	synonymous	Exon 18 of 19	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.1590G>A	p.Ala530Ala	synonymous	Exon 18 of 19	ENSP00000221283.4	Q15833-1
	STXBP2	ENST00000414284.6	TSL:1	c.1581G>A	p.Ala527Ala	synonymous	Exon 18 of 19	ENSP00000409471.1	Q15833-2
	STXBP2	ENST00000597068.5	TSL:1	n.*338G>A		non_coding_transcript_exon	Exon 18 of 19	ENSP00000471327.1	M0R0M7

Frequencies

GnomAD3 genomes AF: 0.00839 AC: 1277 AN: 152172 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.0294

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00222

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00236 AC: 584 AN: 247822 AF XY: 0.00158

Gnomad AFR exome AF: 0.0326

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000537

Gnomad OTH exome AF: 0.000994

GnomAD4 exome AF: 0.000904 AC: 1321 AN: 1461166 Hom.: 19 Cov.: 77 AF XY: 0.000776 AC XY: 564 AN XY: 726890

African (AFR) AF: 0.0321 AC: 1074 AN: 33478

American (AMR) AF: 0.00199 AC: 89 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52848

Middle Eastern (MID) AF: 0.00296 AC: 17 AN: 5740

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1111932

Other (OTH) AF: 0.00164 AC: 99 AN: 60370

GnomAD4 genome AF: 0.00844 AC: 1285 AN: 152290 Hom.: 16 Cov.: 33 AF XY: 0.00818 AC XY: 609 AN XY: 74476

African (AFR) AF: 0.0295 AC: 1225 AN: 41552

American (AMR) AF: 0.00216 AC: 33 AN: 15304

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

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

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.0171 AC: 5 AN: 292

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68020

Other (OTH) AF: 0.00615 AC: 13 AN: 2114

Alfa AF: 0.00449 Hom.: 1

Bravo AF: 0.00943

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely 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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.0040
DANN	Benign	0.40
PhyloP100		-6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=100/0	polymorphism

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: rs61736589; hg19: chr19-7712291;