Genetic Variant NM_006949.4:c.1026+35G>A (chr19-7643083-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_006949.4(STXBP2):c.1026+35G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00236 in 1,614,008 control chromosomes in the GnomAD database, including 76 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.012 ( 36 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 40 hom. )

Consequence

STXBP2
NM_006949.4 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.394

Publications

1 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: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 19-7643083-G-A is Benign according to our data. Variant chr19-7643083-G-A is described in ClinVar as Benign. ClinVar VariationId is 260082.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0122 (1856/152290) while in subpopulation AFR AF = 0.0415 (1724/41540). AF 95% confidence interval is 0.0399. There are 36 homozygotes in GnomAd4. There are 871 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 36 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STXBP2	NM_006949.4 link	c.1026+35G>A		intron_variant	Intron 12 of 18	ENST00000221283.10	NP_008880.2	Q15833-1Q53GF4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STXBP2	ENST00000221283.10 link	c.1026+35G>A		intron_variant	Intron 12 of 18	1	NM_006949.4	ENSP00000221283.4		Q15833-1
ENSG00000268400	ENST00000698368.1 link	n.*1129+35G>A		intron_variant	Intron 14 of 19			ENSP00000513686.1		A0A8V8TM65

Frequencies

GnomAD3 genomes

AF:

0.0122

AC:

1851

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0415

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00596

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.0115

GnomAD2 exomes

AF:

0.00325

AC:

818

AN:

251316

AF XY:

0.00230

show subpopulations

Gnomad AFR exome

AF:

0.0431

Gnomad AMR exome

AF:

0.00188

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.000326

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000194

Gnomad OTH exome

AF:

0.00277

GnomAD4 exome

AF:

0.00133

AC:

1949

AN:

1461718

Hom.:

Cov.:

AF XY:

0.00114

AC XY:

828

AN XY:

727154

show subpopulations

African (AFR)

AF:

0.0434

AC:

1453

AN:

33476

American (AMR)

AF:

0.00233

AC:

104

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.000230

AC:

AN:

26136

East Asian (EAS)

AF:

0.000126

AC:

AN:

39700

South Asian (SAS)

AF:

0.000197

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53368

Middle Eastern (MID)

AF:

0.00867

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000881

AC:

AN:

1111906

Other (OTH)

AF:

0.00358

AC:

216

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

124

249

373

498

622

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

184

230

<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

AF:

0.0122

AC:

1856

AN:

152290

Hom.:

Cov.:

AF XY:

0.0117

AC XY:

871

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.0415

AC:

1724

AN:

41540

American (AMR)

AF:

0.00595

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.000414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68024

Other (OTH)

AF:

0.0114

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

192

288

384

480

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00688

Hom.:

Bravo

AF:

0.0145

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.54

(source)

DANN

Benign

0.76

PhyloP100

-0.39

PromoterAI

0.0038

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over