19-7637178-T-C

Position:

• chr19-7637178-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000221283.10(STXBP2):​c.29T>C​(p.Val10Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. V10V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: STXBP2 ENST00000221283.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.95

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32742104).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STXBP2	NM_006949.4	c.29T>C	p.Val10Ala	missense_variant	1/19	ENST00000221283.10	NP_008880.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STXBP2	ENST00000221283.10	c.29T>C	p.Val10Ala	missense_variant	1/19	1	NM_006949.4	ENSP00000221283	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1089874 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 514890

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 19, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with STXBP2-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change replaces valine with alanine at codon 10 of the STXBP2 protein (p.Val10Ala). The valine residue is moderately conserved and there is a small physicochemical difference between valine and alanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Uncertain	0.094	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	.;.;T;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.77	T;T;T;T
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.33	T;T;T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.1	.;M;M;M
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.7	.;D;D;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.016	.;D;D;D
Sift4G	Uncertain	0.049	D;D;D;D
Polyphen		0.0, 0.0010	.;.;B;B
Vest4		0.64, 0.64, 0.61
MutPred		0.36		Gain of disorder (P = 0.056);Gain of disorder (P = 0.056);Gain of disorder (P = 0.056);Gain of disorder (P = 0.056);
MVP		0.74
MPC		0.29
ClinPred		0.91	D
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.56
gMVP		0.54

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

Publications

LitVar

Other links and lift over

dbSNP: rs2098942359; hg19: chr19-7702064;