14-24855938-C-T

Position:

• chr14-24855938-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001394410.1(STXBP6):​c.449G>A​(p.Gly150Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: STXBP6 NM_001394410.1 missense, splice_region
• Scores: Splicing: ADA: 0.9242
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.25

Genes affected

STXBP6 (HGNC:19666): (syntaxin binding protein 6) Enables cadherin binding activity involved in cell-cell adhesion. Predicted to be involved in Golgi to plasma membrane transport and exocytosis. Located in adherens junction. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35970965).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STXBP6	NM_001394410.1	c.449G>A	p.Gly150Glu	missense_variant, splice_region_variant	4/6	ENST00000323944.10	NP_001381339.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STXBP6	ENST00000323944.10	c.449G>A	p.Gly150Glu	missense_variant, splice_region_variant	4/6	1	NM_001394410.1	ENSP00000324302.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 10, 2024

The c.449G>A (p.G150E) alteration is located in exon 4 (coding exon 3) of the STXBP6 gene. This alteration results from a G to A substitution at nucleotide position 449, causing the glycine (G) at amino acid position 150 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.015	T;T;T;T;T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	.;.;.;.;D
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.36	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;L;L;L;L
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	0.47	N;N;N;N;N
REVEL	Benign	0.084
Sift	Benign	0.23	T;T;T;T;T
Sift4G	Uncertain	0.010	D;D;D;D;D
Polyphen		0.88	P;P;P;P;P
Vest4		0.54
MutPred		0.41		Gain of helix (P = 0.0225);Gain of helix (P = 0.0225);Gain of helix (P = 0.0225);Gain of helix (P = 0.0225);Gain of helix (P = 0.0225);
MVP		0.16
MPC		0.27
ClinPred		0.85	D
GERP RS		5.2
Varity_R		0.16
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.92
dbscSNV1_RF	Pathogenic	0.74
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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-25325144; COSMIC: COSV100122335;