9-127612242-G-GCTCGCGCCGCGCC

Variant names:

• chr9-127612242-G-GCTCGCGCCGCGCC
• rs556763394
• ENST00000635950.2:n.-160_-148dupTCGCGCCGCGCCC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The ENST00000713763.1(STXBP1):​n.-160_-148dupTCGCGCCGCGCCC variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 589,374 control chromosomes in the GnomAD database, including 5 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0050 (4 hom., cov: 30)
  • Exomes 𝑓: 0.00019 (1 hom.)
• Consequence: STXBP1 ENST00000713763.1 non_coding_transcript_exon
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.505
• 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• 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 -10 ACMG points.

• BP6: Variant 9-127612242-G-GCTCGCGCCGCGCC is Benign according to our data. Variant chr9-127612242-G-GCTCGCGCCGCGCC is described in ClinVar as [Likely_benign]. Clinvar id is 1195695.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.005 (739/147738) while in subpopulation AFR AF = 0.0167 (682/40902). AF 95% confidence interval is 0.0156. There are 4 homozygotes in GnomAd4. There are 354 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STXBP1	NM_003165.6	c.-162_-161insCTCGCGCCGCGCC		upstream_gene_variant		ENST00000373302.8	NP_003156.1
STXBP1	NM_001032221.6	c.-162_-161insCTCGCGCCGCGCC		upstream_gene_variant		ENST00000373299.5	NP_001027392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STXBP1	ENST00000373302.8	c.-162_-161insCTCGCGCCGCGCC		upstream_gene_variant		1	NM_003165.6	ENSP00000362399.3
STXBP1	ENST00000373299.5	c.-162_-161insCTCGCGCCGCGCC		upstream_gene_variant		1	NM_001032221.6	ENSP00000362396.2

Frequencies

GnomAD3 genomes AF: 0.00500 AC: 738 AN: 147628 Hom.: 4 Cov.: 30

Gnomad AFR AF: 0.0167

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00349

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: 0.00

Gnomad OTH AF: 0.00245

GnomAD4 exome AF: 0.000195 AC: 86 AN: 441636 Hom.: 1 Cov.: 8 AF XY: 0.000179 AC XY: 40 AN XY: 223806

African (AFR) AF: 0.00901 AC: 70 AN: 7768

American (AMR) AF: 0.000889 AC: 3 AN: 3376

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5830

East Asian (EAS) AF: 0.00 AC: 0 AN: 10794

South Asian (SAS) AF: 0.00 AC: 0 AN: 19404

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 14406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1178

European-Non Finnish (NFE) AF: 0.00000277 AC: 1 AN: 360980

Other (OTH) AF: 0.000670 AC: 12 AN: 17900

GnomAD4 genome AF: 0.00500 AC: 739 AN: 147738 Hom.: 4 Cov.: 30 AF XY: 0.00492 AC XY: 354 AN XY: 71998

African (AFR) AF: 0.0167 AC: 682 AN: 40902

American (AMR) AF: 0.00349 AC: 52 AN: 14914

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3406

East Asian (EAS) AF: 0.00 AC: 0 AN: 4970

South Asian (SAS) AF: 0.00 AC: 0 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9156

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66336

Other (OTH) AF: 0.00242 AC: 5 AN: 2062

Alfa AF: 0.00379 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 27, 2018

GeneDx

Significance: Likely benign

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
PhyloP100		0.51

Splicing

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

Other links and lift over

dbSNP: rs556763394; hg19: chr9-130374521;