chr6-147206022-G-C

Variant names:

• chr6-147206022-G-C
• NM_001127715.4:c.202G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001127715.4(STXBP5):​c.202G>C​(p.Val68Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: STXBP5 NM_001127715.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.60
• Publications: 0 publications found

Genes affected

STXBP5 (HGNC:19665): (syntaxin binding protein 5) Syntaxin 1 is a component of the 7S and 20S SNARE complexes which are involved in docking and fusion of synaptic vesicles with the presynaptic plasma membrane. This gene encodes a syntaxin 1 binding protein. In rat, a similar protein dissociates syntaxin 1 from the Munc18/n-Sec1/rbSec1 complex to form a 10S complex, an intermediate which can be converted to the 7S SNARE complex. Thus this protein is thought to be involved in neurotransmitter release by stimulating SNARE complex formation. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127715.4. 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
	STXBP5	NM_001127715.4	MANE Select	c.202G>C	p.Val68Leu	missense	Exon 2 of 28	NP_001121187.1	Q5T5C0-1
	STXBP5	NM_001394409.1		c.202G>C	p.Val68Leu	missense	Exon 2 of 27	NP_001381338.1	H0Y332
	STXBP5	NM_139244.6		c.202G>C	p.Val68Leu	missense	Exon 2 of 26	NP_640337.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STXBP5	ENST00000321680.11	TSL:5 MANE Select	c.202G>C	p.Val68Leu	missense	Exon 2 of 28	ENSP00000321826.6	Q5T5C0-1
	STXBP5	ENST00000367481.7	TSL:1	c.202G>C	p.Val68Leu	missense	Exon 2 of 26	ENSP00000356451.3	Q5T5C0-2
	STXBP5	ENST00000546097.5	TSL:1	c.310G>C	p.Val104Leu	missense	Exon 2 of 10	ENSP00000441479.2	F6VFW0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.66	D
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.6	L
PhyloP100		9.6
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.29
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.011	D
Polyphen		0.90	P
Vest4		0.74
MutPred		0.41		Loss of ubiquitination at K70 (P = 0.0573)
MVP		0.46
MPC		0.69
ClinPred		0.93	D
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.54
gMVP		0.47
Mutation Taster		=28/72	disease causing

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

hg19: chr6-147527158;