rs117761837

Variant names:

• chr19-7643172-C-T
• rs117761837
• NM_006949.4:c.1034C>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.1034C>T​(p.Thr345Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0139 in 1,614,038 control chromosomes in the GnomAD database, including 209 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T345S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.010 (13 hom., cov: 32)
  • Exomes 𝑓: 0.014 (196 hom.)
• Consequence: STXBP2 NM_006949.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 7.80
• Publications: 20 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, 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=0.018442452).
• BP6: Variant 19-7643172-C-T is Benign according to our data. Variant chr19-7643172-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 194241.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 = 0.0101 (1534/152280) while in subpopulation NFE AF = 0.0162 (1105/68020). AF 95% confidence interval is 0.0154. There are 13 homozygotes in GnomAd4. There are 676 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 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.1034C>T	p.Thr345Met	missense	Exon 13 of 19	NP_008880.2	Q15833-1
	STXBP2	NM_001272034.2		c.1067C>T	p.Thr356Met	missense	Exon 13 of 19	NP_001258963.1	Q15833-3
	STXBP2	NM_001127396.3		c.1025C>T	p.Thr342Met	missense	Exon 13 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.1034C>T	p.Thr345Met	missense	Exon 13 of 19	ENSP00000221283.4	Q15833-1
	STXBP2	ENST00000414284.6	TSL:1	c.1025C>T	p.Thr342Met	missense	Exon 13 of 19	ENSP00000409471.1	Q15833-2
	ENSG00000268400	ENST00000698368.1		n.*1137C>T		non_coding_transcript_exon	Exon 15 of 20	ENSP00000513686.1	A0A8V8TM65

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1538 AN: 152162 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00287

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00681

Gnomad ASJ AF: 0.0274

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00585

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0163

Gnomad OTH AF: 0.0119

GnomAD2 exomes AF: 0.0108 AC: 2708 AN: 251274 AF XY: 0.0108

Gnomad AFR exome AF: 0.00234

Gnomad AMR exome AF: 0.00619

Gnomad ASJ exome AF: 0.0243

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00588

Gnomad NFE exome AF: 0.0163

Gnomad OTH exome AF: 0.0156

GnomAD4 exome AF: 0.0143 AC: 20900 AN: 1461758 Hom.: 196 Cov.: 36 AF XY: 0.0144 AC XY: 10435 AN XY: 727174

African (AFR) AF: 0.00260 AC: 87 AN: 33478

American (AMR) AF: 0.00675 AC: 302 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0253 AC: 661 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.00444 AC: 383 AN: 86252

European-Finnish (FIN) AF: 0.00592 AC: 316 AN: 53362

Middle Eastern (MID) AF: 0.0328 AC: 189 AN: 5768

European-Non Finnish (NFE) AF: 0.0163 AC: 18108 AN: 1111954

Other (OTH) AF: 0.0141 AC: 851 AN: 60392

GnomAD4 genome AF: 0.0101 AC: 1534 AN: 152280 Hom.: 13 Cov.: 32 AF XY: 0.00908 AC XY: 676 AN XY: 74460

African (AFR) AF: 0.00286 AC: 119 AN: 41560

American (AMR) AF: 0.00673 AC: 103 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0274 AC: 95 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.00352 AC: 17 AN: 4826

European-Finnish (FIN) AF: 0.00585 AC: 62 AN: 10596

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0162 AC: 1105 AN: 68020

Other (OTH) AF: 0.0118 AC: 25 AN: 2116

Alfa AF: 0.0136 Hom.: 29

Bravo AF: 0.0103

TwinsUK AF: 0.0173 AC: 64

ALSPAC AF: 0.0179 AC: 69

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.0162 AC: 139

ExAC AF: 0.0109 AC: 1318

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0160

EpiControl AF: 0.0160

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D
MetaRNN	Benign	0.018	T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		7.8
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.028	D
Sift4G	Uncertain	0.024	D
Polyphen		1.0	D
Vest4		0.34
MPC		0.86
ClinPred		0.0072	T
GERP RS		4.3
PromoterAI		-0.027	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.55
gMVP		0.45
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs117761837; hg19: chr19-7708058; COSMIC: COSV108782882; COSMIC: COSV108782882;