19-7642081-T-C

Position:

• chr19-7642081-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_006949.4(STXBP2):​c.626T>C​(p.Leu209Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: STXBP2 NM_006949.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.88

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 19-7642081-T-C is Pathogenic according to our data. Variant chr19-7642081-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 7861.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STXBP2	NM_006949.4	c.626T>C	p.Leu209Pro	missense_variant	8/19	ENST00000221283.10	NP_008880.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STXBP2	ENST00000221283.10	c.626T>C	p.Leu209Pro	missense_variant	8/19	1	NM_006949.4	ENSP00000221283.4
ENSG00000268400	ENST00000698368.1	n.*729T>C		non_coding_transcript_exon_variant	10/20			ENSP00000513686.1
ENSG00000268400	ENST00000698368.1	n.*729T>C		3_prime_UTR_variant	10/20			ENSP00000513686.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 5, WITHOUT MICROVILLUS INCLUSION DISEASE Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	.;.;D;.
Eigen	Uncertain	0.36
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.85	T;D;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Pathogenic	3.6	.;.;H;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-6.2	.;D;D;D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	.;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;.;D;D
Vest4		0.99, 0.99, 0.99
MutPred		0.95		.;.;Gain of disorder (P = 0.0122);.;
MVP		0.94
MPC		1.1
ClinPred		1.0	D
GERP RS		3.3
Varity_R		0.99
gMVP		0.98

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: rs121918541; hg19: chr19-7706967;