19-7647164-C-T

Position:

• chr19-7647164-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_006949.4(STXBP2):​c.1455C>T​(p.Asp485Asp) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,611,710 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0016 (5 hom.)
• Consequence: STXBP2 NM_006949.4 splice_region, synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: -0.274

Genes affected

STXBP2 (HGNC:11445): (syntaxin binding protein 2) This gene encodes a member of the STXBP/unc-18/SEC1 family. The encoded protein is involved in intracellular trafficking, control of SNARE (soluble NSF attachment protein receptor) complex assembly, and the release of cytotoxic granules by natural killer cells. Mutations in this gene are associated with familial hemophagocytic lymphohistiocytosis. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Jan 2013]

ENSG00000268400 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 19-7647164-C-T is Benign according to our data. Variant chr19-7647164-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 330557.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}. Variant chr19-7647164-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.274 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00139 (211/152336) while in subpopulation NFE AF= 0.00206 (140/68016). AF 95% confidence interval is 0.00178. There are 0 homozygotes in gnomad4. There are 99 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STXBP2	NM_006949.4	c.1455C>T	p.Asp485Asp	splice_region_variant, synonymous_variant	17/19	ENST00000221283.10	NP_008880.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STXBP2	ENST00000221283.10	c.1455C>T	p.Asp485Asp	splice_region_variant, synonymous_variant	17/19	1	NM_006949.4	ENSP00000221283.4
ENSG00000268400	ENST00000698368.1	n.*1558C>T		splice_region_variant, non_coding_transcript_exon_variant	19/20			ENSP00000513686.1
ENSG00000268400	ENST00000698368.1	n.*1558C>T		3_prime_UTR_variant	19/20			ENSP00000513686.1

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 211 AN: 152218 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00263

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00206

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00110 AC: 268 AN: 242620 Hom.: 0 AF XY: 0.00106 AC XY: 141 AN XY: 132696

Gnomad AFR exome AF: 0.000331

Gnomad AMR exome AF: 0.000785

Gnomad ASJ exome AF: 0.000305

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00216

Gnomad NFE exome AF: 0.00169

Gnomad OTH exome AF: 0.000837

GnomAD4 exome AF: 0.00156 AC: 2283 AN: 1459374 Hom.: 5 Cov.: 30 AF XY: 0.00155 AC XY: 1126 AN XY: 726024

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.000850

Gnomad4 ASJ exome AF: 0.000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00278

Gnomad4 NFE exome AF: 0.00177

Gnomad4 OTH exome AF: 0.00176

GnomAD4 genome AF: 0.00139 AC: 211 AN: 152336 Hom.: 0 Cov.: 34 AF XY: 0.00133 AC XY: 99 AN XY: 74486

Gnomad4 AFR AF: 0.000288

Gnomad4 AMR AF: 0.00189

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00263

Gnomad4 NFE AF: 0.00206

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00150 Hom.: 0

Bravo AF: 0.00113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 5 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Autoinflammatory syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 01, 2019

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

STXBP2: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.51
DANN	Benign	0.54
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs146425381; hg19: chr19-7712050;