9-127676750-C-T

Position:

• chr9-127676750-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003165.6(STXBP1):​c.1356C>T​(p.Thr452=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00259 in 1,613,476 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0082 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (12 hom.)
• Consequence: STXBP1 NM_003165.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.10

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 9-127676750-C-T is Benign according to our data. Variant chr9-127676750-C-T is described in ClinVar as [Benign]. Clinvar id is 139351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.1 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00821 (1250/152288) while in subpopulation AFR AF= 0.0255 (1059/41554). AF 95% confidence interval is 0.0242. There are 11 homozygotes in gnomad4. There are 579 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1250 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STXBP1	NM_003165.6	c.1356C>T	p.Thr452=	synonymous_variant	15/20	ENST00000373302.8	NP_003156.1
STXBP1	NM_001032221.6	c.1356C>T	p.Thr452=	synonymous_variant	15/19	ENST00000373299.5	NP_001027392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STXBP1	ENST00000373302.8	c.1356C>T	p.Thr452=	synonymous_variant	15/20	1	NM_003165.6	ENSP00000362399	P3
STXBP1	ENST00000373299.5	c.1356C>T	p.Thr452=	synonymous_variant	15/19	1	NM_001032221.6	ENSP00000362396	A1

Frequencies

GnomAD3 genomes AF: 0.00821 AC: 1249 AN: 152170 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0255

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00438

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00147

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00278 AC: 691 AN: 248830 Hom.: 6 AF XY: 0.00226 AC XY: 304 AN XY: 134708

Gnomad AFR exome AF: 0.0254

Gnomad AMR exome AF: 0.00177

Gnomad ASJ exome AF: 0.00380

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000233

Gnomad NFE exome AF: 0.00144

Gnomad OTH exome AF: 0.00329

GnomAD4 exome AF: 0.00200 AC: 2925 AN: 1461188 Hom.: 12 Cov.: 31 AF XY: 0.00187 AC XY: 1357 AN XY: 726822

Gnomad4 AFR exome AF: 0.0265

Gnomad4 AMR exome AF: 0.00224

Gnomad4 ASJ exome AF: 0.00318

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000207

Gnomad4 NFE exome AF: 0.00149

Gnomad4 OTH exome AF: 0.00291

GnomAD4 genome AF: 0.00821 AC: 1250 AN: 152288 Hom.: 11 Cov.: 32 AF XY: 0.00778 AC XY: 579 AN XY: 74464

Gnomad4 AFR AF: 0.0255

Gnomad4 AMR AF: 0.00438

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00147

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00378 Hom.: 4

Bravo AF: 0.00946

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00180

EpiControl AF: 0.00148

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 18, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 28, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	0.082
DANN	Benign	0.91

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

Publications

LitVar

Other links and lift over

dbSNP: rs35099393; hg19: chr9-130439029;