rs199827018

Variant names:

• chr9-127660022-A-G
• rs199827018
• NM_003165.6:c.247-8A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001032221.6(STXBP1):​c.247-8A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00387 in 1,613,778 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0039 (18 hom.)
• Consequence: STXBP1 NM_001032221.6 splice_region, intron
• Scores: Splicing: ADA: 0.00002704
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.467
• Publications: 1 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 9-127660022-A-G is Benign according to our data. Variant chr9-127660022-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 139344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 18 AD,AR gene

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.247-8A>G		splice_region intron	N/A	NP_003156.1	P61764-2
	STXBP1	NM_001032221.6	MANE Select	c.247-8A>G		splice_region intron	N/A	NP_001027392.1	P61764-1
	STXBP1	NM_001374306.2		c.247-8A>G		splice_region intron	N/A	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.247-8A>G		splice_region intron	N/A	ENSP00000362399.3	P61764-2
	STXBP1	ENST00000373299.5	TSL:1 MANE Select	c.247-8A>G		splice_region intron	N/A	ENSP00000362396.2	P61764-1
	STXBP1	ENST00000944186.1		c.266A>G	p.His89Arg	missense	Exon 5 of 19	ENSP00000614245.1

Frequencies

GnomAD3 genomes AF: 0.00315 AC: 478 AN: 151844 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000581

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00462

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000832

Gnomad FIN AF: 0.00928

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00430

Gnomad OTH AF: 0.00288

GnomAD2 exomes AF: 0.00359 AC: 902 AN: 251460 AF XY: 0.00338

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.00496

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00896

Gnomad NFE exome AF: 0.00448

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00394 AC: 5766 AN: 1461816 Hom.: 18 Cov.: 31 AF XY: 0.00382 AC XY: 2780 AN XY: 727206

African (AFR) AF: 0.000747 AC: 25 AN: 33480

American (AMR) AF: 0.00248 AC: 111 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00471 AC: 123 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00146 AC: 126 AN: 86258

European-Finnish (FIN) AF: 0.00865 AC: 462 AN: 53416

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00425 AC: 4726 AN: 1111948

Other (OTH) AF: 0.00313 AC: 189 AN: 60392

GnomAD4 genome AF: 0.00314 AC: 477 AN: 151962 Hom.: 0 Cov.: 31 AF XY: 0.00337 AC XY: 250 AN XY: 74268

African (AFR) AF: 0.000579 AC: 24 AN: 41448

American (AMR) AF: 0.00216 AC: 33 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00462 AC: 16 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.000832 AC: 4 AN: 4806

European-Finnish (FIN) AF: 0.00928 AC: 98 AN: 10556

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

European-Non Finnish (NFE) AF: 0.00430 AC: 292 AN: 67954

Other (OTH) AF: 0.00237 AC: 5 AN: 2108

Alfa AF: 0.00369 Hom.: 0

Bravo AF: 0.00254

EpiCase AF: 0.00365

EpiControl AF: 0.00320

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	1	Developmental and epileptic encephalopathy (1)
-	-	1	Developmental and epileptic encephalopathy, 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.99
DANN	Benign	0.38
PhyloP100		-0.47
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000027
dbscSNV1_RF	Benign	0.0020
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: rs199827018; hg19: chr9-130422301;