rs1554776842

Variant names:

• chr9-127660079-AC-A
• rs1554776842
• NM_003165.6:c.298delC

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+12 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 12 classification points (ACMG Germline Pathogenicity v2019). PVS1PM2PP5_Moderate

The NM_001032221.6(STXBP1):c.298delC (p.Arg100GlyfsTer20) variant causes a frameshift change. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: STXBP1 NM_001032221.6 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.30
• Publications: 0 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, G2P, Labcorp Genetics (formerly Invitae)
• 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

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PVS1Null variant in LOF gene		Frameshift/stop-gained, NMD predicted, LoF disease mechanism — very strong (PVS1); Frameshift (exon 5 of 19) at amino acid 100 of 594, predicted to trigger nonsense-mediated mRNA decay. Loss of function is a known disease mechanism for this gene. A new stop codon is introduced in the shifted frame, truncating the protein to ~118 amino acids (476 amino acids lost).
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 moderate.
	PP5Reputable source reports pathogenic		ClinVar 1-star pathogenic — moderate (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 1 star(s).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001032221.6. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	STXBP1 NM_003165.6	MANE Plus Clinical	c.298delC p.Arg100GlyfsTer20	frameshift	Exon 5 of 20	Prot: NP_003156.1 UniProt:
	STXBP1 NM_001032221.6	MANE Select	c.298delC p.Arg100GlyfsTer20	frameshift	Exon 5 of 19	Prot: NP_001027392.1 UniProt:
	STXBP1 NM_001374306.2		c.298delC p.Arg100GlyfsTer17	frameshift	Exon 5 of 19	Prot: NP_001361235.1

STXBP1 NM_003165.6

MANE Plus Clinical

HGVSc / HGVSpc.298delCp.Arg100GlyfsTer20

Exon rankExon 5 of 20

frameshift

Prot: NP_003156.1UniProt: P61764-2

STXBP1 NM_001032221.6

MANE Select

HGVSc / HGVSpc.298delCp.Arg100GlyfsTer20

Exon rankExon 5 of 19

frameshift

Prot: NP_001027392.1UniProt: P61764-1

STXBP1 NM_001374306.2

HGVSc / HGVSpc.298delCp.Arg100GlyfsTer17

Exon rankExon 5 of 19

frameshift

Prot: NP_001361235.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	STXBP1 ENST00000373302.8	TSL:1MANE Plus Clinical	c.298delC p.Arg100GlyfsTer20	frameshift	Exon 5 of 20	Prot: ENSP00000362399.3 UniProt:
	STXBP1 ENST00000373299.5	TSL:1MANE Select	c.298delC p.Arg100GlyfsTer20	frameshift	Exon 5 of 19	Prot: ENSP00000362396.2 UniProt:
	STXBP1 ENST00000494254.4	TSL:5	c.298delC p.Arg100GlyfsTer20	frameshift	Exon 5 of 19	Prot: ENSP00000485397.2 UniProt:

STXBP1 ENST00000373302.8

TSL:1MANE Plus Clinical

HGVSc / HGVSpc.298delCp.Arg100GlyfsTer20

Exon rankExon 5 of 20

frameshift

Prot: ENSP00000362399.3UniProt: P61764-2

STXBP1 ENST00000373299.5

TSL:1MANE Select

HGVSc / HGVSpc.298delCp.Arg100GlyfsTer20

Exon rankExon 5 of 19

frameshift

Prot: ENSP00000362396.2UniProt: P61764-1

STXBP1 ENST00000494254.4

TSL:5

HGVSc / HGVSpc.298delCp.Arg100GlyfsTer20

Exon rankExon 5 of 19

frameshift

Prot: ENSP00000485397.2UniProt: P61764-2A0A096LP52

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Inborn genetic diseases (1)
1	-	-	Infantile epilepsy syndrome (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
Mutation Taster	N/A	1/199	disease causing (ClinVar)
PhyloP100	Benign	1.3

Showing 2 of 2 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
SpliceAI score (max)	Benign	0.030	Details are displayed if max score is > 0.2

Showing 1 of 1 scores

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs1554776842;

hg19: chr9-130422358;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar