9-127651572-CCTCT-CCT

Variant names:

• chr9-127651572-CCT-C
• rs755475986
• NM_003165.6:c.38-16_38-15delCT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_001032221.6(STXBP1):​c.38-16_38-15delCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0105 in 1,217,174 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 31)
  • Exomes 𝑓: 0.012 (0 hom.)
• Consequence: STXBP1 NM_001032221.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0900
• 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 -8 ACMG points.

• BP6: Variant 9-127651572-CCT-C is Benign according to our data. Variant chr9-127651572-CCT-C is described in ClinVar as [Benign]. Clinvar id is 207401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STXBP1	NM_003165.6	c.38-16_38-15delCT		intron_variant	Intron 1 of 19	ENST00000373302.8	NP_003156.1
STXBP1	NM_001032221.6	c.38-16_38-15delCT		intron_variant	Intron 1 of 18	ENST00000373299.5	NP_001027392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STXBP1	ENST00000373302.8	c.38-30_38-29delCT		intron_variant	Intron 1 of 19	1	NM_003165.6	ENSP00000362399.3
STXBP1	ENST00000373299.5	c.38-30_38-29delCT		intron_variant	Intron 1 of 18	1	NM_001032221.6	ENSP00000362396.2

Frequencies

GnomAD3 genomes AF: 0.000598 AC: 90 AN: 150408 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000976

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000930

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00206

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000133

Gnomad OTH AF: 0.00290

GnomAD2 exomes AF: 0.00823 AC: 1097 AN: 133350 AF XY: 0.00873

Gnomad AFR exome AF: 0.00615

Gnomad AMR exome AF: 0.00730

Gnomad ASJ exome AF: 0.00434

Gnomad EAS exome AF: 0.00651

Gnomad FIN exome AF: 0.0120

Gnomad NFE exome AF: 0.00831

Gnomad OTH exome AF: 0.00823

GnomAD4 exome AF: 0.0119 AC: 12704 AN: 1066654 Hom.: 0 AF XY: 0.0114 AC XY: 5991 AN XY: 525876

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0121 AC: 298 AN: 24616

American (AMR) AF: 0.00832 AC: 268 AN: 32224

Ashkenazi Jewish (ASJ) AF: 0.0128 AC: 228 AN: 17854

East Asian (EAS) AF: 0.0113 AC: 312 AN: 27520

South Asian (SAS) AF: 0.00667 AC: 371 AN: 55652

European-Finnish (FIN) AF: 0.0123 AC: 488 AN: 39730

Middle Eastern (MID) AF: 0.0110 AC: 50 AN: 4566

European-Non Finnish (NFE) AF: 0.0123 AC: 10139 AN: 821040

Other (OTH) AF: 0.0127 AC: 550 AN: 43452

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000598 AC: 90 AN: 150520 Hom.: 0 Cov.: 31 AF XY: 0.000667 AC XY: 49 AN XY: 73480

African (AFR) AF: 0.000973 AC: 40 AN: 41116

American (AMR) AF: 0.000929 AC: 14 AN: 15066

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3450

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.00 AC: 0 AN: 4758

European-Finnish (FIN) AF: 0.00206 AC: 21 AN: 10190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.000133 AC: 9 AN: 67512

Other (OTH) AF: 0.00287 AC: 6 AN: 2088

Alfa AF: 0.0687 Hom.: 0

Bravo AF: 0.000472

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Mar 19, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is found in EPILEPSY,INFANT-EPI panel(s). -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.090
Mutation Taster		=100/0	polymorphism

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: rs755475986; hg19: chr9-130413851; COSMIC: COSV64812772; COSMIC: COSV64812772;