rs181216956

Variant names:

• chr19-7641772-C-T
• rs181216956
• NM_006949.4:c.497C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_006949.4(STXBP2):​c.497C>T​(p.Thr166Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000233 in 1,551,858 control chromosomes in the GnomAD database, including 1 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T166T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00022 (1 hom.)
• Consequence: STXBP2 NM_006949.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.07
• Publications: 3 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

ENSG00000268400 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009160012).
• BP6: Variant 19-7641772-C-T is Benign according to our data. Variant chr19-7641772-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 436896.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000394 (60/152324) while in subpopulation EAS AF = 0.011 (57/5172). AF 95% confidence interval is 0.00873. There are 0 homozygotes in GnomAd4. There are 31 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.497C>T	p.Thr166Met	missense	Exon 7 of 19	NP_008880.2
	STXBP2	NM_001272034.2		c.530C>T	p.Thr177Met	missense	Exon 7 of 19	NP_001258963.1
	STXBP2	NM_001127396.3		c.488C>T	p.Thr163Met	missense	Exon 7 of 19	NP_001120868.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STXBP2	ENST00000221283.10	TSL:1 MANE Select	c.497C>T	p.Thr166Met	missense	Exon 7 of 19	ENSP00000221283.4
	STXBP2	ENST00000414284.6	TSL:1	c.488C>T	p.Thr163Met	missense	Exon 7 of 19	ENSP00000409471.1
	STXBP2	ENST00000597068.5	TSL:1	n.497C>T		non_coding_transcript_exon	Exon 7 of 19	ENSP00000471327.1

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0112

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00115 AC: 180 AN: 157034 AF XY: 0.00124

Gnomad AFR exome AF: 0.000113

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0156

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000165

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000216 AC: 302 AN: 1399534 Hom.: 1 Cov.: 32 AF XY: 0.000220 AC XY: 152 AN XY: 690444

African (AFR) AF: 0.0000948 AC: 3 AN: 31632

American (AMR) AF: 0.00 AC: 0 AN: 35806

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25174

East Asian (EAS) AF: 0.00769 AC: 276 AN: 35896

South Asian (SAS) AF: 0.0000378 AC: 3 AN: 79272

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49330

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4752

European-Non Finnish (NFE) AF: 0.0000120 AC: 13 AN: 1079718

Other (OTH) AF: 0.000121 AC: 7 AN: 57954

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152324 Hom.: 0 Cov.: 33 AF XY: 0.000416 AC XY: 31 AN XY: 74482

African (AFR) AF: 0.0000241 AC: 1 AN: 41576

American (AMR) AF: 0.00 AC: 0 AN: 15306

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

East Asian (EAS) AF: 0.0110 AC: 57 AN: 5172

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000135 Hom.: 1

Bravo AF: 0.000487

ExAC AF: 0.000288 AC: 30

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	12
DANN	Benign	0.93
DEOGEN2	Benign	0.14	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	0.0092	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.1
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.13
Sift	Benign	0.13	T
Sift4G	Benign	0.12	T
Polyphen		0.022	B
Vest4		0.11
MVP		0.56
MPC		0.25
ClinPred		0.014	T
GERP RS		-2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.3
Varity_R		0.035
gMVP		0.38
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs181216956; hg19: chr19-7706658;