NM_006949.4:c.*12G>A

Variant names:

• chr19-7647822-G-A
• rs28464386
• NM_006949.4:c.*12G>A

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.*12G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00513 in 1,344,010 control chromosomes in the GnomAD database, including 202 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (97 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (105 hom.)
• Consequence: STXBP2 NM_006949.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.528
• Publications: 4 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 19-7647822-G-A is Benign according to our data. Variant chr19-7647822-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260080.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0737 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STXBP2	NM_006949.4	MANE Select	c.*12G>A		3_prime_UTR	Exon 19 of 19	NP_008880.2
	STXBP2	NR_073560.2		n.1809G>A		non_coding_transcript_exon	Exon 19 of 19
	STXBP2	NM_001272034.2		c.*12G>A		3_prime_UTR	Exon 19 of 19	NP_001258963.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STXBP2	ENST00000221283.10	TSL:1 MANE Select	c.*12G>A		3_prime_UTR	Exon 19 of 19	ENSP00000221283.4
	STXBP2	ENST00000414284.6	TSL:1	c.*12G>A		3_prime_UTR	Exon 19 of 19	ENSP00000409471.1
	STXBP2	ENST00000595800.1	TSL:2	n.1924G>A		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.0224 AC: 3229 AN: 144248 Hom.: 97 Cov.: 32

Gnomad AFR AF: 0.0759

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00948

Gnomad ASJ AF: 0.00119

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000473

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00325

Gnomad NFE AF: 0.000718

Gnomad OTH AF: 0.0126

GnomAD2 exomes AF: 0.00606 AC: 1512 AN: 249452 AF XY: 0.00452

Gnomad AFR exome AF: 0.0760

Gnomad AMR exome AF: 0.00542

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.0000547

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000605

Gnomad OTH exome AF: 0.00295

GnomAD4 exome AF: 0.00305 AC: 3663 AN: 1199644 Hom.: 105 Cov.: 32 AF XY: 0.00269 AC XY: 1612 AN XY: 598940

African (AFR) AF: 0.0919 AC: 2550 AN: 27760

American (AMR) AF: 0.00600 AC: 236 AN: 39318

Ashkenazi Jewish (ASJ) AF: 0.00184 AC: 35 AN: 19014

East Asian (EAS) AF: 0.0000446 AC: 1 AN: 22408

South Asian (SAS) AF: 0.000194 AC: 16 AN: 82614

European-Finnish (FIN) AF: 0.0000539 AC: 2 AN: 37134

Middle Eastern (MID) AF: 0.00778 AC: 36 AN: 4626

European-Non Finnish (NFE) AF: 0.000503 AC: 463 AN: 920756

Other (OTH) AF: 0.00704 AC: 324 AN: 46014

GnomAD4 genome AF: 0.0224 AC: 3236 AN: 144366 Hom.: 97 Cov.: 32 AF XY: 0.0217 AC XY: 1520 AN XY: 70158

African (AFR) AF: 0.0759 AC: 3019 AN: 39750

American (AMR) AF: 0.00946 AC: 138 AN: 14582

Ashkenazi Jewish (ASJ) AF: 0.00119 AC: 4 AN: 3354

East Asian (EAS) AF: 0.00 AC: 0 AN: 4538

South Asian (SAS) AF: 0.000473 AC: 2 AN: 4226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9272

Middle Eastern (MID) AF: 0.00350 AC: 1 AN: 286

European-Non Finnish (NFE) AF: 0.000718 AC: 47 AN: 65486

Other (OTH) AF: 0.0125 AC: 25 AN: 2008

Alfa AF: 0.00427 Hom.: 4

Bravo AF: 0.0241

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Familial hemophagocytic lymphohistiocytosis 5 (2)
-	-	1	Autoinflammatory syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.83
DANN	Benign	0.62
PhyloP100		-0.53
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs28464386; hg19: chr19-7712708;