19-7647257-C-T

Variant names:

• chr19-7647257-C-T
• rs139200597
• NM_006949.4:c.1538+10C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006949.4(STXBP2):​c.1538+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00327 in 1,610,392 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0034 (11 hom.)
• Consequence: STXBP2 NM_006949.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.99
• Publications: 1 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 19-7647257-C-T is Benign according to our data. Variant chr19-7647257-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00217 (331/152266) while in subpopulation NFE AF = 0.00357 (243/67992). AF 95% confidence interval is 0.0032. There are 0 homozygotes in GnomAd4. There are 154 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 11 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006949.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STXBP2	NM_006949.4	MANE Select	c.1538+10C>T		intron	N/A	NP_008880.2
	STXBP2	NM_001272034.2		c.1571+10C>T		intron	N/A	NP_001258963.1
	STXBP2	NM_001127396.3		c.1529+10C>T		intron	N/A	NP_001120868.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STXBP2	ENST00000221283.10	TSL:1 MANE Select	c.1538+10C>T		intron	N/A	ENSP00000221283.4
	STXBP2	ENST00000414284.6	TSL:1	c.1529+10C>T		intron	N/A	ENSP00000409471.1
	STXBP2	ENST00000597068.5	TSL:1	n.*286+10C>T		intron	N/A	ENSP00000471327.1

Frequencies

GnomAD3 genomes AF: 0.00218 AC: 332 AN: 152148 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00359

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00176 AC: 414 AN: 235124 AF XY: 0.00180

Gnomad AFR exome AF: 0.000928

Gnomad AMR exome AF: 0.00138

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000113

Gnomad FIN exome AF: 0.000294

Gnomad NFE exome AF: 0.00283

Gnomad OTH exome AF: 0.00260

GnomAD4 exome AF: 0.00339 AC: 4942 AN: 1458126 Hom.: 11 Cov.: 29 AF XY: 0.00324 AC XY: 2353 AN XY: 725384

African (AFR) AF: 0.000688 AC: 23 AN: 33434

American (AMR) AF: 0.00143 AC: 64 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26048

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.00158 AC: 136 AN: 86156

European-Finnish (FIN) AF: 0.000137 AC: 7 AN: 51080

Middle Eastern (MID) AF: 0.00161 AC: 9 AN: 5602

European-Non Finnish (NFE) AF: 0.00406 AC: 4507 AN: 1111230

Other (OTH) AF: 0.00324 AC: 195 AN: 60254

GnomAD4 genome AF: 0.00217 AC: 331 AN: 152266 Hom.: 0 Cov.: 33 AF XY: 0.00207 AC XY: 154 AN XY: 74462

African (AFR) AF: 0.000866 AC: 36 AN: 41564

American (AMR) AF: 0.00248 AC: 38 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5162

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4826

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00357 AC: 243 AN: 67992

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00126 Hom.: 0

Bravo AF: 0.00208

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Familial hemophagocytic lymphohistiocytosis 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.019
DANN	Benign	0.81
PhyloP100		-2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	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: rs139200597; hg19: chr19-7712143;