rs145304925

Variant names:

• chr9-127682406-C-T
• rs145304925
• NM_003165.6:c.1548C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_001032221.6(STXBP1):​c.1548C>T​(p.Ser516Ser) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00237 in 1,613,966 control chromosomes in the GnomAD database, including 10 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 0.0015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0025 (10 hom.)
• Consequence: STXBP1 NM_001032221.6 splice_region, synonymous
• Scores: Splicing: ADA: 0.0001158
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.530
• Publications: 2 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 9-127682406-C-T is Benign according to our data. Variant chr9-127682406-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.53 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 10 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.1548C>T	p.Ser516Ser	splice_region synonymous	Exon 18 of 20	NP_003156.1	P61764-2
	STXBP1	NM_001032221.6	MANE Select	c.1548C>T	p.Ser516Ser	splice_region synonymous	Exon 18 of 19	NP_001027392.1	P61764-1
	STXBP1	NM_001374306.2		c.1539C>T	p.Ser513Ser	splice_region 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.1548C>T	p.Ser516Ser	splice_region synonymous	Exon 18 of 20	ENSP00000362399.3	P61764-2
	STXBP1	ENST00000373299.5	TSL:1 MANE Select	c.1548C>T	p.Ser516Ser	splice_region synonymous	Exon 18 of 19	ENSP00000362396.2	P61764-1
	STXBP1	ENST00000494254.4	TSL:5	c.1548C>T	p.Ser516Ser	splice_region synonymous	Exon 18 of 19	ENSP00000485397.2	A0A096LP52

Frequencies

GnomAD3 genomes AF: 0.00148 AC: 226 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00290

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00134 AC: 336 AN: 251040 AF XY: 0.00133

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00249

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.00246 AC: 3595 AN: 1461644 Hom.: 10 Cov.: 31 AF XY: 0.00241 AC XY: 1755 AN XY: 727134

African (AFR) AF: 0.000269 AC: 9 AN: 33480

American (AMR) AF: 0.000402 AC: 18 AN: 44724

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

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00121 AC: 104 AN: 86256

European-Finnish (FIN) AF: 0.000113 AC: 6 AN: 53194

Middle Eastern (MID) AF: 0.00278 AC: 16 AN: 5758

European-Non Finnish (NFE) AF: 0.00301 AC: 3346 AN: 1112002

Other (OTH) AF: 0.00157 AC: 95 AN: 60394

GnomAD4 genome AF: 0.00148 AC: 226 AN: 152322 Hom.: 0 Cov.: 33 AF XY: 0.00134 AC XY: 100 AN XY: 74478

African (AFR) AF: 0.000361 AC: 15 AN: 41580

American (AMR) AF: 0.000588 AC: 9 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00290 AC: 197 AN: 68020

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00184 Hom.: 0

Bravo AF: 0.00144

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00256

EpiControl AF: 0.00284

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	2	Developmental and epileptic encephalopathy, 4 (2)
-	-	1	Developmental and epileptic encephalopathy (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	13
DANN	Benign	0.77
PhyloP100		0.53
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.050
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: rs145304925; hg19: chr9-130444685;