rs370053399

chr19-7641843-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006949.4(STXBP2):c.568C>T(p.Arg190Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000529 in 1,554,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R190H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00054 (0 hom.)
• Consequence: STXBP2 NM_006949.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:1 O:1
• Conservation: PhyloP100: 1.85

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23708275).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STXBP2	NM_006949.4	c.568C>T	p.Arg190Cys	missense_variant	7/19	ENST00000221283.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STXBP2	ENST00000221283.10	c.568C>T	p.Arg190Cys	missense_variant	7/19	1	NM_006949.4	P4

Frequencies

GnomAD3 genomes AF: 0.000407 AC: 62 AN: 152188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000483 AC: 76 AN: 157426 Hom.: 0 AF XY: 0.000415 AC XY: 35 AN XY: 84258

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000795

Gnomad ASJ exome AF: 0.00237

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000129

Gnomad FIN exome AF: 0.0000647

Gnomad NFE exome AF: 0.000786

Gnomad OTH exome AF: 0.000450

GnomAD4 exome AF: 0.000542 AC: 760 AN: 1402616 Hom.: 0 Cov.: 32 AF XY: 0.000526 AC XY: 364 AN XY: 692330

Gnomad4 AFR exome AF: 0.0000316

Gnomad4 AMR exome AF: 0.0000828

Gnomad4 ASJ exome AF: 0.00250

Gnomad4 EAS exome AF: 0.0000278

Gnomad4 SAS exome AF: 0.0000376

Gnomad4 FIN exome AF: 0.000163

Gnomad4 NFE exome AF: 0.000595

Gnomad4 OTH exome AF: 0.000637

GnomAD4 genome AF: 0.000407 AC: 62 AN: 152306 Hom.: 0 Cov.: 33 AF XY: 0.000389 AC XY: 29 AN XY: 74476

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000706

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000914 Hom.: 0

Bravo AF: 0.000348

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000366 AC: 3

ExAC AF: 0.000214 AC: 24

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 5 Uncertain:3 Benign:1 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	STXBP2 NM_006949 exon 7 p.Arg190Cys (c.568C>T): This variant has been reported in the literature in 1 individual with hemophagocytic lymphohistiocytosis as a double heterozygote (Zhang 2014 PMID:24916509). This variant is present in 0.2% (21/8488) of Ashkenazi Jewish alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs370053399). This variant is present in ClinVar (Variation ID:404841). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 26, 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	May 28, 2016	- -
not provided, no classification provided	literature only	GeneReviews	-	Dominant-negative variant assoc w/fHLH in 1 infant [Benavides et al 2020] -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 11, 2018	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 19, 2024

Variant summary: FANCC c.568C>T (p.Leu190Phe) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251376 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.568C>T has been reported in the literature in individuals affected with Fanconi Anemia Group C. These report(s) do not provide unequivocal conclusions about association of the variant with Fanconi Anemia Group C. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Pathogenic	0.19
Cadd	Pathogenic	34
Dann	Uncertain	1.0
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.24	T;T;T;T
MetaSVM	Uncertain	0.16	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.69	T
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	.;.;D;D
Vest4		0.72, 0.72
MVP		0.91
MPC		0.44
ClinPred		0.38	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.84
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs370053399; hg19: chr19-7706729;