chr19-7637178-T-TG

Variant names:

• chr19-7637178-T-TG
• rs1269457253
• NM_006949.4:c.34dupG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_006949.4(STXBP2):​c.34dupG​(p.Glu12GlyfsTer42) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 151,304 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. E12E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: STXBP2 NM_006949.4 frameshift, splice_region
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.170
• Publications: 0 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]

ENSG00000268400 (HGNC:):

PCP2 (HGNC:30209): (Purkinje cell protein 2) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of catalytic activity. Predicted to act upstream of or within rhodopsin mediated signaling pathway. Predicted to be located in neuronal cell body. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 74 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-7637178-T-TG is Pathogenic according to our data. Variant chr19-7637178-T-TG is described in ClinVar as Pathogenic. ClinVar VariationId is 2840748.Status of the report is criteria_provided_single_submitter, 1 stars.

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.34dupG	p.Glu12GlyfsTer42	frameshift splice_region	Exon 1 of 19	NP_008880.2	Q15833-1
	STXBP2	NM_001272034.2		c.34dupG	p.Glu12GlyfsTer42	frameshift splice_region	Exon 1 of 19	NP_001258963.1	Q15833-3
	STXBP2	NM_001127396.3		c.34dupG	p.Glu12GlyfsTer42	frameshift splice_region	Exon 1 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.34dupG	p.Glu12GlyfsTer42	frameshift splice_region	Exon 1 of 19	ENSP00000221283.4	Q15833-1
	STXBP2	ENST00000414284.6	TSL:1	c.34dupG	p.Glu12GlyfsTer42	frameshift splice_region	Exon 1 of 19	ENSP00000409471.1	Q15833-2
	STXBP2	ENST00000597068.5	TSL:1	n.34dupG		splice_region non_coding_transcript_exon	Exon 1 of 19	ENSP00000471327.1	M0R0M7

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151304 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000487

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1089872 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 514890

African (AFR) AF: 0.00 AC: 0 AN: 22980

American (AMR) AF: 0.00 AC: 0 AN: 8408

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14370

East Asian (EAS) AF: 0.00 AC: 0 AN: 26522

South Asian (SAS) AF: 0.00 AC: 0 AN: 19886

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29952

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3694

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 920274

Other (OTH) AF: 0.00 AC: 0 AN: 43786

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151304 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 73870

African (AFR) AF: 0.0000487 AC: 2 AN: 41104

American (AMR) AF: 0.00 AC: 0 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

South Asian (SAS) AF: 0.00 AC: 0 AN: 4764

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67798

Other (OTH) AF: 0.00 AC: 0 AN: 2076

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Familial hemophagocytic lymphohistiocytosis 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.17
Mutation Taster		=4/196	disease causing (fs/PTC)

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: rs1269457253; hg19: chr19-7702064;