rs6791

Variant names:

• chr19-7647391-A-G
• rs6791
• NM_006949.4:c.1576A>G

Your query was ambiguous. Multiple possible variants found:

• chr19-7647391-A-G
• chr19-7647391-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006949.4(STXBP2):​c.1576A>G​(p.Ile526Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.63 in 1,613,250 control chromosomes in the GnomAD database, including 324,031 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I526L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.67 (35051 hom., cov: 33)
  • Exomes 𝑓: 0.63 (288980 hom.)
• Consequence: STXBP2 NM_006949.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: -0.234
• Publications: 59 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 (MetaRNN=9.451353E-7).
• BP6: Variant 19-7647391-A-G is Benign according to our data. Variant chr19-7647391-A-G is described in ClinVar as Benign. ClinVar VariationId is 260094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.803 is higher than 0.05.

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.1576A>G	p.Ile526Val	missense	Exon 18 of 19	NP_008880.2	Q15833-1
	STXBP2	NM_001272034.2		c.1609A>G	p.Ile537Val	missense	Exon 18 of 19	NP_001258963.1	Q15833-3
	STXBP2	NM_001127396.3		c.1567A>G	p.Ile523Val	missense	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.1576A>G	p.Ile526Val	missense	Exon 18 of 19	ENSP00000221283.4	Q15833-1
	STXBP2	ENST00000414284.6	TSL:1	c.1567A>G	p.Ile523Val	missense	Exon 18 of 19	ENSP00000409471.1	Q15833-2
	STXBP2	ENST00000597068.5	TSL:1	n.*324A>G		non_coding_transcript_exon	Exon 18 of 19	ENSP00000471327.1	M0R0M7

Frequencies

GnomAD3 genomes AF: 0.673 AC: 102229 AN: 151992 Hom.: 35002 Cov.: 33

Gnomad AFR AF: 0.772

Gnomad AMI AF: 0.689

Gnomad AMR AF: 0.675

Gnomad ASJ AF: 0.505

Gnomad EAS AF: 0.824

Gnomad SAS AF: 0.506

Gnomad FIN AF: 0.735

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.612

Gnomad OTH AF: 0.648

GnomAD2 exomes AF: 0.634 AC: 156856 AN: 247224 AF XY: 0.623

Gnomad AFR exome AF: 0.776

Gnomad AMR exome AF: 0.647

Gnomad ASJ exome AF: 0.510

Gnomad EAS exome AF: 0.815

Gnomad FIN exome AF: 0.728

Gnomad NFE exome AF: 0.613

Gnomad OTH exome AF: 0.635

GnomAD4 exome AF: 0.625 AC: 913822 AN: 1461140 Hom.: 288980 Cov.: 88 AF XY: 0.621 AC XY: 451111 AN XY: 726860

African (AFR) AF: 0.783 AC: 26215 AN: 33478

American (AMR) AF: 0.655 AC: 29274 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.509 AC: 13288 AN: 26130

East Asian (EAS) AF: 0.849 AC: 33698 AN: 39700

South Asian (SAS) AF: 0.492 AC: 42473 AN: 86248

European-Finnish (FIN) AF: 0.721 AC: 38079 AN: 52786

Middle Eastern (MID) AF: 0.537 AC: 3085 AN: 5740

European-Non Finnish (NFE) AF: 0.620 AC: 689438 AN: 1111960

Other (OTH) AF: 0.634 AC: 38272 AN: 60378

GnomAD4 genome AF: 0.673 AC: 102340 AN: 152110 Hom.: 35051 Cov.: 33 AF XY: 0.676 AC XY: 50271 AN XY: 74366

African (AFR) AF: 0.772 AC: 32043 AN: 41490

American (AMR) AF: 0.674 AC: 10319 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.505 AC: 1750 AN: 3468

East Asian (EAS) AF: 0.823 AC: 4254 AN: 5166

South Asian (SAS) AF: 0.507 AC: 2441 AN: 4816

European-Finnish (FIN) AF: 0.735 AC: 7794 AN: 10606

Middle Eastern (MID) AF: 0.510 AC: 150 AN: 294

European-Non Finnish (NFE) AF: 0.612 AC: 41588 AN: 67948

Other (OTH) AF: 0.651 AC: 1375 AN: 2112

Alfa AF: 0.625 Hom.: 61574

Bravo AF: 0.678

TwinsUK AF: 0.632 AC: 2345

ALSPAC AF: 0.616 AC: 2375

ESP6500AA AF: 0.775 AC: 3404

ESP6500EA AF: 0.612 AC: 5251

ExAC AF: 0.632 AC: 76700

Asia WGS AF: 0.676 AC: 2352 AN: 3478

EpiCase AF: 0.609

EpiControl AF: 0.602

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	Familial hemophagocytic lymphohistiocytosis 5 (4)
-	-	1	Familial hemophagocytic lymphohistiocytosis (1)
-	-	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.028
DANN	Benign	0.25
DEOGEN2	Benign	0.058	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.060	T
MetaRNN	Benign	9.5e-7	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.75	N
PhyloP100		-0.23
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.59	N
REVEL	Benign	0.11
Sift	Benign	0.54	T
Sift4G	Benign	0.63	T
Polyphen		0.0	B
Vest4		0.010
MPC		0.20
ClinPred		0.0018	T
GERP RS		-0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.025
gMVP		0.26
Mutation Taster		=98/2	polymorphism (auto)

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: rs6791; hg19: chr19-7712277; COSMIC: COSV55401668; COSMIC: COSV55401668;