rs1862514

Variant names:

• chr19-7633434-C-T
• rs1862514
• NM_174895.3:c.24G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-7633434-C-T
• chr19-7633434-C-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_174895.3(PCP2):​c.24G>A​(p.Thr8Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.341 in 1,575,464 control chromosomes in the GnomAD database, including 94,726 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (7063 hom., cov: 33)
  • Exomes 𝑓: 0.35 (87663 hom.)
• Consequence: PCP2 NM_174895.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0410
• Publications: 14 publications found

Genes affected

PCP2 (HGNC:30209): (Purkinje cell protein 2) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of catalytic activity. Predicted to act upstream of or within rhodopsin mediated signaling pathway. Predicted to be located in neuronal cell body. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000268400 (HGNC:):

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: AD, AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, ClinGen, PanelApp Australia, 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 19-7633434-C-T is Benign according to our data. Variant chr19-7633434-C-T is described in ClinVar as Benign. ClinVar VariationId is 403501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.041 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.363 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_174895.3. 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
	PCP2	NM_174895.3	MANE Select	c.24G>A	p.Thr8Thr	synonymous	Exon 1 of 4	NP_777555.1	Q8IVA1-1
	STXBP2	NM_001414484.1		c.-60+2588C>T		intron	N/A	NP_001401413.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCP2	ENST00000311069.6	TSL:1 MANE Select	c.24G>A	p.Thr8Thr	synonymous	Exon 1 of 4	ENSP00000310585.4	Q8IVA1-1
	ENSG00000268400	ENST00000698368.1		n.114+2775C>T		intron	N/A	ENSP00000513686.1	A0A8V8TM65
	ENSG00000268400	ENST00000595866.2	TSL:5	n.138+2588C>T		intron	N/A	ENSP00000469553.2	M0QY33

Frequencies

GnomAD3 genomes AF: 0.290 AC: 44039 AN: 151720 Hom.: 7056 Cov.: 33

Gnomad AFR AF: 0.164

Gnomad AMI AF: 0.209

Gnomad AMR AF: 0.245

Gnomad ASJ AF: 0.270

Gnomad EAS AF: 0.195

Gnomad SAS AF: 0.290

Gnomad FIN AF: 0.417

Gnomad MID AF: 0.290

Gnomad NFE AF: 0.367

Gnomad OTH AF: 0.298

GnomAD2 exomes AF: 0.297 AC: 55860 AN: 187902 AF XY: 0.304

Gnomad AFR exome AF: 0.158

Gnomad AMR exome AF: 0.190

Gnomad ASJ exome AF: 0.259

Gnomad EAS exome AF: 0.182

Gnomad FIN exome AF: 0.413

Gnomad NFE exome AF: 0.360

Gnomad OTH exome AF: 0.330

GnomAD4 exome AF: 0.346 AC: 492828 AN: 1423624 Hom.: 87663 Cov.: 39 AF XY: 0.345 AC XY: 243371 AN XY: 704550

African (AFR) AF: 0.156 AC: 5143 AN: 32890

American (AMR) AF: 0.197 AC: 7740 AN: 39206

Ashkenazi Jewish (ASJ) AF: 0.266 AC: 6755 AN: 25386

East Asian (EAS) AF: 0.190 AC: 7280 AN: 38268

South Asian (SAS) AF: 0.288 AC: 23401 AN: 81240

European-Finnish (FIN) AF: 0.408 AC: 20686 AN: 50678

Middle Eastern (MID) AF: 0.291 AC: 1661 AN: 5712

European-Non Finnish (NFE) AF: 0.367 AC: 400926 AN: 1091348

Other (OTH) AF: 0.327 AC: 19236 AN: 58896

GnomAD4 genome AF: 0.290 AC: 44059 AN: 151840 Hom.: 7063 Cov.: 33 AF XY: 0.290 AC XY: 21564 AN XY: 74236

African (AFR) AF: 0.164 AC: 6772 AN: 41388

American (AMR) AF: 0.245 AC: 3746 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.270 AC: 936 AN: 3464

East Asian (EAS) AF: 0.195 AC: 1006 AN: 5150

South Asian (SAS) AF: 0.290 AC: 1396 AN: 4814

European-Finnish (FIN) AF: 0.417 AC: 4411 AN: 10568

Middle Eastern (MID) AF: 0.296 AC: 87 AN: 294

European-Non Finnish (NFE) AF: 0.367 AC: 24879 AN: 67872

Other (OTH) AF: 0.302 AC: 636 AN: 2104

Alfa AF: 0.331 Hom.: 17195

Bravo AF: 0.269

Asia WGS AF: 0.250 AC: 873 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	3.2
DANN	Benign	0.61
PhyloP100		0.041
PromoterAI		-0.0080	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1862514; hg19: chr19-7698320; COSMIC: COSV55403018; COSMIC: COSV55403018;