9-127669958-G-C

Variant names:

• chr9-127669958-G-C
• rs1554777932
• NM_003165.6:c.963G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The NM_001032221.6(STXBP1):​c.963G>C​(p.Lys321Asn) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: STXBP1 NM_001032221.6 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.66

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the STXBP1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 106 curated pathogenic missense variants (we use a threshold of 10). The gene has 79 curated benign missense variants. Gene score misZ: 4.263 (above the threshold of 3.09). Trascript score misZ: 5.8379 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability, autosomal dominant non-syndromic intellectual disability, Dravet syndrome, undetermined early-onset epileptic encephalopathy, autism spectrum disorder, developmental and epileptic encephalopathy, West syndrome, atypical Rett syndrome, developmental and epileptic encephalopathy, 4.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STXBP1	NM_003165.6	c.963G>C	p.Lys321Asn	missense_variant, splice_region_variant	Exon 11 of 20	ENST00000373302.8	NP_003156.1
STXBP1	NM_001032221.6	c.963G>C	p.Lys321Asn	missense_variant, splice_region_variant	Exon 11 of 19	ENST00000373299.5	NP_001027392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STXBP1	ENST00000373302.8	c.963G>C	p.Lys321Asn	missense_variant, splice_region_variant	Exon 11 of 20	1	NM_003165.6	ENSP00000362399.3
STXBP1	ENST00000373299.5	c.963G>C	p.Lys321Asn	missense_variant, splice_region_variant	Exon 11 of 19	1	NM_001032221.6	ENSP00000362396.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jul 28, 2016

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Benign	0.0014	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.079	.;T;.;T;.;T;D
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;.;D;D;D;D;D
M_CAP	Benign	0.067	D
MetaRNN	Uncertain	0.49	T;T;T;T;T;T;T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	1.6	.;.;L;.;.;.;L
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.5	.;.;D;.;.;.;D
REVEL	Uncertain	0.39
Sift	Benign	0.047	.;.;D;.;.;.;D
Sift4G	Benign	0.11	.;.;T;.;.;.;T
Polyphen		0.18, 0.014	.;.;B;.;.;.;B
Vest4		0.45, 0.46
MutPred		0.47		.;.;Loss of ubiquitination at K321 (P = 0.0047);Loss of ubiquitination at K321 (P = 0.0047);Loss of ubiquitination at K321 (P = 0.0047);.;Loss of ubiquitination at K321 (P = 0.0047);
MVP		0.61
MPC		1.9
ClinPred		0.97	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.71
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.92		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.92		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554777932; hg19: chr9-130432237;