NM_006949.4:c.49G>A

Variant names:

• chr19-7638737-G-A
• rs146165014
• NM_006949.4:c.49G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_006949.4(STXBP2):​c.49G>A​(p.Gly17Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000446 in 1,614,150 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: STXBP2 NM_006949.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:4
• Conservation: PhyloP100: 8.94
• 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: AD, AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, ClinGen, PanelApp Australia, 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009026319).
• BP6: Variant 19-7638737-G-A is Benign according to our data. Variant chr19-7638737-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 260106.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00246 (374/152264) while in subpopulation AFR AF = 0.0084 (349/41550). AF 95% confidence interval is 0.00767. There are 1 homozygotes in GnomAd4. There are 179 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STXBP2	NM_006949.4	MANE Select	c.49G>A	p.Gly17Arg	missense	Exon 2 of 19	NP_008880.2	Q15833-1
	STXBP2	NM_001272034.2		c.49G>A	p.Gly17Arg	missense	Exon 2 of 19	NP_001258963.1	Q15833-3
	STXBP2	NM_001127396.3		c.49G>A	p.Gly17Arg	missense	Exon 2 of 19	NP_001120868.1	Q15833-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STXBP2	ENST00000221283.10	TSL:1 MANE Select	c.49G>A	p.Gly17Arg	missense	Exon 2 of 19	ENSP00000221283.4	Q15833-1
	STXBP2	ENST00000414284.6	TSL:1	c.49G>A	p.Gly17Arg	missense	Exon 2 of 19	ENSP00000409471.1	Q15833-2
	STXBP2	ENST00000597068.5	TSL:1	n.49G>A		non_coding_transcript_exon	Exon 2 of 19	ENSP00000471327.1	M0R0M7

Frequencies

GnomAD3 genomes AF: 0.00245 AC: 373 AN: 152146 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00840

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000983

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000700 AC: 176 AN: 251462 AF XY: 0.000478

Gnomad AFR exome AF: 0.00984

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000237 AC: 346 AN: 1461886 Hom.: 0 Cov.: 33 AF XY: 0.000195 AC XY: 142 AN XY: 727246

African (AFR) AF: 0.00902 AC: 302 AN: 33480

American (AMR) AF: 0.000402 AC: 18 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112006

Other (OTH) AF: 0.000315 AC: 19 AN: 60396

GnomAD4 genome AF: 0.00246 AC: 374 AN: 152264 Hom.: 1 Cov.: 33 AF XY: 0.00240 AC XY: 179 AN XY: 74466

African (AFR) AF: 0.00840 AC: 349 AN: 41550

American (AMR) AF: 0.000981 AC: 15 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68016

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.000983 Hom.: 0

Bravo AF: 0.00290

ESP6500AA AF: 0.00840 AC: 37

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000898 AC: 109

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not specified (4)
-	1	1	Familial hemophagocytic lymphohistiocytosis 5 (2)
-	1	-	Autoinflammatory syndrome (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.019	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.091	D
MetaRNN	Benign	0.0090	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	1.9	M
PhyloP100		8.9
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.77	N
REVEL	Uncertain	0.43
Sift	Benign	0.063	T
Sift4G	Benign	0.073	T
Polyphen		0.88	P
Vest4		0.63
MutPred		0.37		Gain of MoRF binding (P = 0.0225)
MVP		0.91
MPC		0.95
ClinPred		0.028	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.36
gMVP		0.66
Mutation Taster		=34/66	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs146165014; hg19: chr19-7703623; COSMIC: COSV99657295; COSMIC: COSV99657295;