chr19-7644673-C-G

Variant names:

• chr19-7644673-C-G
• rs139160342
• NM_006949.4:c.1167C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006949.4(STXBP2):​c.1167C>G​(p.Ile389Met) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I389I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: STXBP2 NM_006949.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.48
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30820692).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STXBP2	NM_006949.4	c.1167C>G	p.Ile389Met	missense_variant	Exon 14 of 19	ENST00000221283.10	NP_008880.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STXBP2	ENST00000221283.10	c.1167C>G	p.Ile389Met	missense_variant	Exon 14 of 19	1	NM_006949.4	ENSP00000221283.4
ENSG00000268400	ENST00000698368.1	n.*1270C>G		non_coding_transcript_exon_variant	Exon 16 of 20			ENSP00000513686.1
ENSG00000268400	ENST00000698368.1	n.*1270C>G		3_prime_UTR_variant	Exon 16 of 20			ENSP00000513686.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	0.13
DANN	Benign	0.94
DEOGEN2	Benign	0.26	.;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.20	N
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.31	T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.6	.;L;.
PhyloP100		-1.5
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.0	N;N;N
REVEL	Uncertain	0.57
Sift	Benign	0.13	T;T;T
Sift4G	Benign	0.15	T;T;T
Polyphen		0.29, 0.24	.;B;B
Vest4		0.51
MutPred		0.72		.;Loss of catalytic residue at L394 (P = 0.0521);.;
MVP		0.39
MPC		0.35
ClinPred		0.67	D
GERP RS		-7.1
Varity_R		0.58
gMVP		0.60
Mutation Taster		=52/48	polymorphism

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

Other links and lift over

dbSNP: rs139160342; hg19: chr19-7709559;