dbSNP rs61407177: STXBP2:c.1247-10C>A (chr19-7645187-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_006949.4(STXBP2):c.1247-10C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000214 in 1,402,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

STXBP2
NM_006949.4 intron

Scores

Splicing: ADA: 0.9768

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.77

Publications

0 publications found

Variant links:

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

STXBP2 links:

ENSG00000268400 (HGNC:):

ENSG00000268400 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STXBP2	NM_006949.4 link	c.1247-10C>A		intron_variant	Intron 14 of 18	ENST00000221283.10	NP_008880.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STXBP2	ENST00000221283.10 link	c.1247-10C>A		intron_variant	Intron 14 of 18	1	NM_006949.4	ENSP00000221283.4
ENSG00000268400	ENST00000698368.1 link	n.*1350-10C>A		intron_variant	Intron 16 of 19			ENSP00000513686.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000214

AC:

AN:

1402952

Hom.:

Cov.:

AF XY:

0.00000289

AC XY:

AN XY:

692404

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31818

American (AMR)

AF:

0.00

AC:

AN:

36254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25240

East Asian (EAS)

AF:

0.0000553

AC:

AN:

36144

South Asian (SAS)

AF:

0.00

AC:

AN:

79598

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49426

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

9.25e-7

AC:

AN:

1080608

Other (OTH)

AF:

0.00

AC:

AN:

58162

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

2.9

(source)

DANN

Benign

0.51

PhyloP100

-1.8

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Pathogenic

0.99

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.98

Position offset: 2

DS_AL_spliceai

0.56

Position offset: 10

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over