9-127612422-A-G

Variant names:

• chr9-127612422-A-G
• rs2132275587
• NM_003165.6:c.19A>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_001032221.6(STXBP1):​c.19A>G​(p.Lys7Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K7R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: STXBP1 NM_001032221.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: -0.233
• 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):

• developmental and epileptic encephalopathy, 4

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 9 uncertain in NM_001032221.6
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-127612422-A-G is Pathogenic according to our data. Variant chr9-127612422-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1389624.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STXBP1	NM_003165.6	c.19A>G	p.Lys7Glu	missense_variant	Exon 1 of 20	ENST00000373302.8	NP_003156.1
STXBP1	NM_001032221.6	c.19A>G	p.Lys7Glu	missense_variant	Exon 1 of 19	ENST00000373299.5	NP_001027392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STXBP1	ENST00000373302.8	c.19A>G	p.Lys7Glu	missense_variant	Exon 1 of 20	1	NM_003165.6	ENSP00000362399.3
STXBP1	ENST00000373299.5	c.19A>G	p.Lys7Glu	missense_variant	Exon 1 of 19	1	NM_001032221.6	ENSP00000362396.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 30

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Seizure Pathogenic:1

Mar 26, 2025

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy Uncertain:1

Feb 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with STXBP1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 7 of the STXBP1 protein (p.Lys7Glu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.089	.;T;.;D;.
Eigen	Uncertain	0.32
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.82	T;T;T;T;.
M_CAP	Pathogenic	0.98	D
MetaRNN	Uncertain	0.69	D;D;D;D;D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Pathogenic	2.9	M;.;.;M;.
PhyloP100		-0.23
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-2.8	D;.;.;D;.
REVEL	Uncertain	0.57
Sift	Uncertain	0.011	D;.;.;D;.
Sift4G	Uncertain	0.0030	D;.;.;D;.
Polyphen		1.0	D;.;.;D;.
Vest4		0.35
MutPred		0.70		Loss of methylation at K7 (P = 0.0088);Loss of methylation at K7 (P = 0.0088);Loss of methylation at K7 (P = 0.0088);Loss of methylation at K7 (P = 0.0088);Loss of methylation at K7 (P = 0.0088);
MVP		0.72
MPC		1.8
ClinPred		0.95	D
GERP RS		2.7
PromoterAI		-0.063	Neutral
Varity_R		0.37
gMVP		0.81
Mutation Taster		=77/23	polymorphism

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: rs2132275587; hg19: chr9-130374701;