rs796053361

Variant names:

• chr9-127668160-G-A
• rs796053361
• NM_003165.6:c.875G>A
• STXBP1 p.Arg292His

Your query was ambiguous. Multiple possible variants found:

• chr9-127668160-G-A
• chr9-127668160-G-C
• chr9-127668160-G-T

Germline classificationCancer classification (beta)

Variant summary

Our verdict is

Pathogenic

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

. The variant received 18 ACMG points: 18P and 0B. PS3PM1PM2PM5PP3_StrongPP5_Strong

The NM_001032221.6(STXBP1):c.875G>A (p.Arg292His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 9.91). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000243251: Published functional studies in C. elegans demonstrated that the transgenic R292H strain exhibited significantly reduced body bends on agar and showed significantly defective locomotion compared to worms expressing wild-type, and STXBP1 protein levels were reduced to 20-30% of wild-type, suggesting the variant results in STXBP1 protein instability (Zhu et al., 2020);". A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.R292P: Likely_pathogenic (ClinVar VariationId 984866, 1 star) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R292= (synonymous): Uncertain_significance (ClinVar VariationId 810417, 1 star); p.R292= (synonymous): Likely_benign (ClinVar VariationId 1082544, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency: Genomes: not found (cov: 32)
• Consequence: STXBP1 NM_001032221.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12 O:1
• Conservation: PhyloP100: 9.91
• Publications: 24 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):

• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• developmental and epileptic encephalopathy, 4

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

Classification according to ACMG Germline Pathogenicity v2019

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

• PS3: Well-established functional study supports damaging effect (PS3); SCV000243251: Published functional studies in C. elegans demonstrated that the transgenic R292H strain exhibited significantly reduced body bends on agar and showed significantly defective locomotion compared to worms expressing wild-type, and STXBP1 protein levels were reduced to 20-30% of wild-type, suggesting the variant results in STXBP1 protein instability (Zhu et al., 2020)
• PM1: Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 8 pathogenic, 1 benign (OR vs. background: 28.3).
• PM2: Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 moderate.
• PM5: Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.R292P: Likely_pathogenic (ClinVar VariationId 984866, 1 star); Other variants at the same amino acid residue (not pathogenic): p.R292= (synonymous): Uncertain_significance (ClinVar VariationId 810417, 1 star); p.R292= (synonymous): Likely_benign (ClinVar VariationId 1082544, 1 star)
• PP3: Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — strong evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Strong).
• PP5: ClinVar 2-star pathogenic — strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s).

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.875G>A	p.Arg292His	missense	Exon 10 of 20	NP_003156.1	P61764-2
	STXBP1	NM_001032221.6	MANE Select	c.875G>A	p.Arg292His	missense	Exon 10 of 19	NP_001027392.1	P61764-1
	STXBP1	NM_001374306.2		c.866G>A	p.Arg289His	missense	Exon 10 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.875G>A	p.Arg292His	missense	Exon 10 of 20	ENSP00000362399.3	P61764-2
	STXBP1	ENST00000373299.5	TSL:1 MANE Select	c.875G>A	p.Arg292His	missense	Exon 10 of 19	ENSP00000362396.2	P61764-1
	STXBP1	ENST00000494254.4	TSL:5	c.875G>A	p.Arg292His	missense	Exon 10 of 19	ENSP00000485397.2	A0A096LP52

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	Developmental and epileptic encephalopathy, 4 (8)
2	-	-	not provided (2)
1	-	-	Early-infantile DEE (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Infantile epilepsy syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.29	T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		9.9
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R		0.85
gMVP		0.99
Mutation Taster		=3/97	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs796053361;

hg19: chr9-130430439;

COSMIC: COSV106535933;

COSMIC: COSV106535933;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar