chr19-7646335-T-C

Variant names:

• chr19-7646335-T-C
• rs10001
• NM_006949.4:c.1443T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006949.4(STXBP2):​c.1443T>C​(p.Asp481Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.389 in 1,605,256 control chromosomes in the GnomAD database, including 125,924 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (14749 hom., cov: 32)
  • Exomes 𝑓: 0.38 (111175 hom.)
• Consequence: STXBP2 NM_006949.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: -1.00
• Publications: 26 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 19-7646335-T-C is Benign according to our data. Variant chr19-7646335-T-C is described in ClinVar as Benign. ClinVar VariationId is 260089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.684 is higher than 0.05.

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.1443T>C	p.Asp481Asp	synonymous	Exon 16 of 19	NP_008880.2	Q15833-1
	STXBP2	NM_001272034.2		c.1476T>C	p.Asp492Asp	synonymous	Exon 16 of 19	NP_001258963.1	Q15833-3
	STXBP2	NM_001127396.3		c.1434T>C	p.Asp478Asp	synonymous	Exon 16 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.1443T>C	p.Asp481Asp	synonymous	Exon 16 of 19	ENSP00000221283.4	Q15833-1
	STXBP2	ENST00000414284.6	TSL:1	c.1434T>C	p.Asp478Asp	synonymous	Exon 16 of 19	ENSP00000409471.1	Q15833-2
	STXBP2	ENST00000597068.5	TSL:1	n.*191T>C		non_coding_transcript_exon	Exon 16 of 19	ENSP00000471327.1	M0R0M7

Frequencies

GnomAD3 genomes AF: 0.433 AC: 65729 AN: 151924 Hom.: 14720 Cov.: 32

Gnomad AFR AF: 0.496

Gnomad AMI AF: 0.208

Gnomad AMR AF: 0.464

Gnomad ASJ AF: 0.310

Gnomad EAS AF: 0.704

Gnomad SAS AF: 0.360

Gnomad FIN AF: 0.527

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.367

Gnomad OTH AF: 0.414

GnomAD2 exomes AF: 0.418 AC: 97048 AN: 232440 AF XY: 0.408

Gnomad AFR exome AF: 0.499

Gnomad AMR exome AF: 0.454

Gnomad ASJ exome AF: 0.303

Gnomad EAS exome AF: 0.683

Gnomad FIN exome AF: 0.509

Gnomad NFE exome AF: 0.366

Gnomad OTH exome AF: 0.401

GnomAD4 exome AF: 0.385 AC: 558921 AN: 1453214 Hom.: 111175 Cov.: 40 AF XY: 0.383 AC XY: 276300 AN XY: 722094

African (AFR) AF: 0.504 AC: 16837 AN: 33426

American (AMR) AF: 0.455 AC: 19509 AN: 42888

Ashkenazi Jewish (ASJ) AF: 0.306 AC: 7948 AN: 25936

East Asian (EAS) AF: 0.720 AC: 28316 AN: 39342

South Asian (SAS) AF: 0.342 AC: 28962 AN: 84714

European-Finnish (FIN) AF: 0.502 AC: 26389 AN: 52608

Middle Eastern (MID) AF: 0.325 AC: 1866 AN: 5750

European-Non Finnish (NFE) AF: 0.366 AC: 405232 AN: 1108428

Other (OTH) AF: 0.397 AC: 23862 AN: 60122

GnomAD4 genome AF: 0.433 AC: 65815 AN: 152042 Hom.: 14749 Cov.: 32 AF XY: 0.440 AC XY: 32696 AN XY: 74334

African (AFR) AF: 0.496 AC: 20575 AN: 41468

American (AMR) AF: 0.464 AC: 7093 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.310 AC: 1076 AN: 3468

East Asian (EAS) AF: 0.703 AC: 3630 AN: 5162

South Asian (SAS) AF: 0.361 AC: 1738 AN: 4818

European-Finnish (FIN) AF: 0.527 AC: 5577 AN: 10590

Middle Eastern (MID) AF: 0.357 AC: 105 AN: 294

European-Non Finnish (NFE) AF: 0.367 AC: 24949 AN: 67948

Other (OTH) AF: 0.418 AC: 882 AN: 2110

Alfa AF: 0.384 Hom.: 6884

Bravo AF: 0.432

Asia WGS AF: 0.529 AC: 1839 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Familial hemophagocytic lymphohistiocytosis 5 (2)
-	-	2	not provided (3)
-	-	1	Familial hemophagocytic lymphohistiocytosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.11
DANN	Benign	0.47
PhyloP100		-1.0
PromoterAI		0.15	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs10001; hg19: chr19-7711221; COSMIC: COSV55403586; COSMIC: COSV55403586;