rs181216956

Positions:

• chr19-7641772-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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

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]

ENSG00000268400 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STXBP2	NM_006949.4	c.497C>T	p.Thr166Met	missense_variant	7/19	ENST00000221283.10	NP_008880.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STXBP2	ENST00000221283.10	c.497C>T	p.Thr166Met	missense_variant	7/19	1	NM_006949.4	ENSP00000221283.4
ENSG00000268400	ENST00000698368.1	n.*600C>T		non_coding_transcript_exon_variant	9/20			ENSP00000513686.1
ENSG00000268400	ENST00000698368.1	n.*600C>T		3_prime_UTR_variant	9/20			ENSP00000513686.1

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

GnomAD3 exomes AF: 0.00115 AC: 180 AN: 157034 Hom.: 1 AF XY: 0.00124 AC XY: 103 AN XY: 82790

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 SAS exome AF: 0.00

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

Gnomad4 AFR exome AF: 0.0000948

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00769

Gnomad4 SAS exome AF: 0.0000378

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000120

Gnomad4 OTH exome AF: 0.000121

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

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0110

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000123 Hom.: 1

Bravo AF: 0.000487

ExAC AF: 0.000288 AC: 30

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 28, 2023	Variant summary: STXBP2 c.497C>T (p.Thr166Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 157034 control chromosomes, predominantly at a frequency of 0.016 within the East Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 7-fold of the estimated maximal expected allele frequency for a pathogenic variant in STXBP2 causing Familial Hemophagocytic Lymphohistiocytosis phenotype (0.0022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.497C>T has been reported in the literature in East Asian individuals affected with Familial Hemophagocytic Lymphohistiocytosis (e.g. Chen_2016, Miao_2019, Zhang_2019, Zhang_2020, Xu_2022), however most reported individuals carried the variant in monoallelic form, and some authors also noted that the frequency of the variant was similar to that found in ethinically matched controls (e.g. Miao_2019). These reports do not provide unequivocal conclusions about association of the variant with Familial Hemophagocytic Lymphohistiocytosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27209435, 30899265, 31388699, 32375849, 35296096). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 12, 2015	- -

Familial hemophagocytic lymphohistiocytosis 5 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

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;T;T;T
MetaRNN	Benign	0.0092	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.1	.;.;L;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.4	.;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.13	.;T;T;T
Sift4G	Benign	0.12	T;T;T;T
Polyphen		0.022, 0.017	.;.;B;B
Vest4		0.11, 0.11, 0.10
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs181216956; hg19: chr19-7706658;