rs796053355

Variant names:

• chr9-127663343-C-T
• rs796053355
• NM_003165.6:c.568C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001032221.6(STXBP1):​c.568C>T​(p.Arg190Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R190Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: STXBP1 NM_001032221.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: 2.40
• Publications: 9 publications found

Genes affected

STXBP1 (HGNC:11444): (syntaxin binding protein 1) This gene encodes a syntaxin-binding protein. The encoded protein appears to play a role in release of neurotransmitters via regulation of syntaxin, a transmembrane attachment protein receptor. Mutations in this gene have been associated with infantile epileptic encephalopathy-4. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2010]

STXBP1 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 4

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• atypical Rett syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Dravet syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autism spectrum disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• intellectual disability

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_001032221.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-127663344-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 207418.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 9-127663343-C-T is Pathogenic according to our data. Variant chr9-127663343-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 207417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001032221.6. 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
	STXBP1	NM_003165.6	MANE Plus Clinical	c.568C>T	p.Arg190Trp	missense	Exon 7 of 20	NP_003156.1	P61764-2
	STXBP1	NM_001032221.6	MANE Select	c.568C>T	p.Arg190Trp	missense	Exon 7 of 19	NP_001027392.1	P61764-1
	STXBP1	NM_001374306.2		c.559C>T	p.Arg187Trp	missense	Exon 7 of 19	NP_001361235.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STXBP1	ENST00000373302.8	TSL:1 MANE Plus Clinical	c.568C>T	p.Arg190Trp	missense	Exon 7 of 20	ENSP00000362399.3	P61764-2
	STXBP1	ENST00000373299.5	TSL:1 MANE Select	c.568C>T	p.Arg190Trp	missense	Exon 7 of 19	ENSP00000362396.2	P61764-1
	STXBP1	ENST00000494254.4	TSL:5	c.568C>T	p.Arg190Trp	missense	Exon 7 of 19	ENSP00000485397.2	A0A096LP52

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461836 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727216

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111992

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Developmental and epileptic encephalopathy, 4 (5)
2	-	-	not provided (2)
1	-	-	Developmental and epileptic encephalopathy (1)
1	-	-	Infantile epilepsy syndrome (1)
1	-	-	Neurodevelopmental delay (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		2.4
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.92		Loss of methylation at R192 (P = 0.1155)
MVP		0.90
MPC		2.5
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.88
gMVP		0.97
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs796053355; hg19: chr9-130425622;