chr19-7647822-G-C

Variant names:

• chr19-7647822-G-C
• rs28464386
• NM_006949.4:c.*12G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000221283.10(STXBP2):​c.*12G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: STXBP2 ENST00000221283.10 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.528
• Publications: 4 publications found

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]

STXBP2 Gene-Disease associations (from GenCC):

• familial hemophagocytic lymphohistiocytosis 5

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• hereditary hemophagocytic lymphohistiocytosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• microvillus inclusion disease

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000221283.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STXBP2	NM_006949.4	MANE Select	c.*12G>C		3_prime_UTR	Exon 19 of 19	NP_008880.2
	STXBP2	NR_073560.2		n.1809G>C		non_coding_transcript_exon	Exon 19 of 19
	STXBP2	NM_001272034.2		c.*12G>C		3_prime_UTR	Exon 19 of 19	NP_001258963.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STXBP2	ENST00000221283.10	TSL:1 MANE Select	c.*12G>C		3_prime_UTR	Exon 19 of 19	ENSP00000221283.4
	STXBP2	ENST00000414284.6	TSL:1	c.*12G>C		3_prime_UTR	Exon 19 of 19	ENSP00000409471.1
	STXBP2	ENST00000595800.1	TSL:2	n.1924G>C		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.00203 AC: 291 AN: 143658 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00116

Gnomad AMR AF: 0.00290

Gnomad ASJ AF: 0.000299

Gnomad EAS AF: 0.0110

Gnomad SAS AF: 0.0104

Gnomad FIN AF: 0.00435

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.000505

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000356 AC: 424 AN: 1192374 Hom.: 0 Cov.: 32 AF XY: 0.000341 AC XY: 203 AN XY: 595246

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

African (AFR) AF: 0.000472 AC: 13 AN: 27550

American (AMR) AF: 0.000282 AC: 11 AN: 39068

Ashkenazi Jewish (ASJ) AF: 0.000642 AC: 12 AN: 18694

East Asian (EAS) AF: 0.00119 AC: 26 AN: 21912

South Asian (SAS) AF: 0.000121 AC: 10 AN: 82524

European-Finnish (FIN) AF: 0.000437 AC: 16 AN: 36624

Middle Eastern (MID) AF: 0.000655 AC: 3 AN: 4578

European-Non Finnish (NFE) AF: 0.000326 AC: 299 AN: 915886

Other (OTH) AF: 0.000747 AC: 34 AN: 45538

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00200 AC: 288 AN: 143782 Hom.: 0 Cov.: 32 AF XY: 0.00213 AC XY: 149 AN XY: 69836

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

African (AFR) AF: 0.00111 AC: 44 AN: 39700

American (AMR) AF: 0.00276 AC: 40 AN: 14512

Ashkenazi Jewish (ASJ) AF: 0.000299 AC: 1 AN: 3346

East Asian (EAS) AF: 0.0111 AC: 49 AN: 4434

South Asian (SAS) AF: 0.0101 AC: 42 AN: 4144

European-Finnish (FIN) AF: 0.00435 AC: 40 AN: 9200

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.00107 AC: 70 AN: 65294

Other (OTH) AF: 0.000500 AC: 1 AN: 2002

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 4

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.0
DANN	Benign	0.58
PhyloP100		-0.53
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs28464386; hg19: chr19-7712708;