9-127682520-C-T

Variant names:

• chr9-127682520-C-T
• rs142595450
• NM_003165.6:c.1662C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6_Very_Strong BP7

The NM_001032221.6(STXBP1):​c.1662C>T​(p.Tyr554Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000166 in 1,614,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: STXBP1 NM_001032221.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.813
• 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: G2P, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 9-127682520-C-T is Benign according to our data. Variant chr9-127682520-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 139354.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.813 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001032221.6. 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
	STXBP1	NM_003165.6	MANE Plus Clinical	c.1662C>T	p.Tyr554Tyr	synonymous	Exon 18 of 20	NP_003156.1	P61764-2
	STXBP1	NM_001032221.6	MANE Select	c.1662C>T	p.Tyr554Tyr	synonymous	Exon 18 of 19	NP_001027392.1	P61764-1
	STXBP1	NM_001374306.2		c.1653C>T	p.Tyr551Tyr	synonymous	Exon 18 of 19	NP_001361235.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STXBP1	ENST00000373302.8	TSL:1 MANE Plus Clinical	c.1662C>T	p.Tyr554Tyr	synonymous	Exon 18 of 20	ENSP00000362399.3	P61764-2
	STXBP1	ENST00000373299.5	TSL:1 MANE Select	c.1662C>T	p.Tyr554Tyr	synonymous	Exon 18 of 19	ENSP00000362396.2	P61764-1
	STXBP1	ENST00000494254.4	TSL:5	c.1662C>T	p.Tyr554Tyr	synonymous	Exon 18 of 19	ENSP00000485397.2	A0A096LP52

Frequencies

GnomAD3 genomes AF: 0.000565 AC: 86 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000215 AC: 54 AN: 251378 AF XY: 0.000199

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000792

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000125 AC: 182 AN: 1461692 Hom.: 0 Cov.: 31 AF XY: 0.000121 AC XY: 88 AN XY: 727148

African (AFR) AF: 0.00114 AC: 38 AN: 33470

American (AMR) AF: 0.000537 AC: 24 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86252

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53348

Middle Eastern (MID) AF: 0.000882 AC: 5 AN: 5672

European-Non Finnish (NFE) AF: 0.0000746 AC: 83 AN: 1112012

Other (OTH) AF: 0.000464 AC: 28 AN: 60378

GnomAD4 genome AF: 0.000565 AC: 86 AN: 152308 Hom.: 0 Cov.: 33 AF XY: 0.000564 AC XY: 42 AN XY: 74480

African (AFR) AF: 0.00135 AC: 56 AN: 41574

American (AMR) AF: 0.00131 AC: 20 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68030

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.000278 Hom.: 0

Bravo AF: 0.000676

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Developmental and epileptic encephalopathy (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	5.2
DANN	Benign	0.74
PhyloP100		-0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7

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: rs142595450; hg19: chr9-130444799; COSMIC: COSV105295428;