19-7647164-C-T

Variant names:

• chr19-7647164-C-T
• rs146425381
• NM_006949.4:c.1455C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_006949.4(STXBP2):​c.1455C>T​(p.Asp485Asp) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,611,710 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0016 (5 hom.)
• Consequence: STXBP2 NM_006949.4 splice_region, synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: -0.274
• Publications: 2 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 19-7647164-C-T is Benign according to our data. Variant chr19-7647164-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 330557.
• BP7: Synonymous conserved (PhyloP=-0.274 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00139 (211/152336) while in subpopulation NFE AF = 0.00206 (140/68016). AF 95% confidence interval is 0.00178. There are 0 homozygotes in GnomAd4. There are 99 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 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.1455C>T	p.Asp485Asp	splice_region synonymous	Exon 17 of 19	NP_008880.2
	STXBP2	NM_001272034.2		c.1488C>T	p.Asp496Asp	splice_region synonymous	Exon 17 of 19	NP_001258963.1
	STXBP2	NM_001127396.3		c.1446C>T	p.Asp482Asp	splice_region synonymous	Exon 17 of 19	NP_001120868.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STXBP2	ENST00000221283.10	TSL:1 MANE Select	c.1455C>T	p.Asp485Asp	splice_region synonymous	Exon 17 of 19	ENSP00000221283.4
	STXBP2	ENST00000414284.6	TSL:1	c.1446C>T	p.Asp482Asp	splice_region synonymous	Exon 17 of 19	ENSP00000409471.1
	STXBP2	ENST00000597068.5	TSL:1	n.*203C>T		splice_region non_coding_transcript_exon	Exon 17 of 19	ENSP00000471327.1

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 211 AN: 152218 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00263

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00206

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00110 AC: 268 AN: 242620 AF XY: 0.00106

Gnomad AFR exome AF: 0.000331

Gnomad AMR exome AF: 0.000785

Gnomad ASJ exome AF: 0.000305

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00216

Gnomad NFE exome AF: 0.00169

Gnomad OTH exome AF: 0.000837

GnomAD4 exome AF: 0.00156 AC: 2283 AN: 1459374 Hom.: 5 Cov.: 30 AF XY: 0.00155 AC XY: 1126 AN XY: 726024

African (AFR) AF: 0.000448 AC: 15 AN: 33452

American (AMR) AF: 0.000850 AC: 38 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.000383 AC: 10 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86222

European-Finnish (FIN) AF: 0.00278 AC: 144 AN: 51790

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5202

European-Non Finnish (NFE) AF: 0.00177 AC: 1969 AN: 1111876

Other (OTH) AF: 0.00176 AC: 106 AN: 60312

GnomAD4 genome AF: 0.00139 AC: 211 AN: 152336 Hom.: 0 Cov.: 34 AF XY: 0.00133 AC XY: 99 AN XY: 74486

African (AFR) AF: 0.000288 AC: 12 AN: 41598

American (AMR) AF: 0.00189 AC: 29 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00263 AC: 28 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00206 AC: 140 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00150 Hom.: 0

Bravo AF: 0.00113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 5 Uncertain:1 Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Autoinflammatory syndrome Uncertain:1

May 01, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Apr 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

STXBP2: BP4, BP7

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.51
DANN	Benign	0.54
PhyloP100		-0.27
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	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: rs146425381; hg19: chr19-7712050;