rs189368660

Variant names:

• chr19-7632826-C-A
• rs189368660
• NM_174895.3:c.56G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_174895.3(PCP2):​c.56G>T​(p.Gly19Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00189 in 1,549,988 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G19C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0040 (15 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (73 hom.)
• Consequence: PCP2 NM_174895.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.386
• Publications: 0 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, 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020546913).
• BP6: Variant 19-7632826-C-A is Benign according to our data. Variant chr19-7632826-C-A is described in ClinVar as Benign. ClinVar VariationId is 770282.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0567 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.56G>T	p.Gly19Val	missense	Exon 2 of 4	NP_777555.1	Q8IVA1-1
	PCP2	NM_001271830.2		c.8G>T	p.Gly3Val	missense	Exon 2 of 4	NP_001258759.1	Q8IVA1-2
	STXBP2	NM_001414484.1		c.-60+1980C>A		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.56G>T	p.Gly19Val	missense	Exon 2 of 4	ENSP00000310585.4	Q8IVA1-1
	ENSG00000268400	ENST00000698368.1		n.114+2167C>A		intron	N/A	ENSP00000513686.1	A0A8V8TM65
	PCP2	ENST00000598935.5	TSL:3	c.8G>T	p.Gly3Val	missense	Exon 2 of 4	ENSP00000472761.1	Q8IVA1-2

Frequencies

GnomAD3 genomes AF: 0.00400 AC: 609 AN: 152130 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0353

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00528

GnomAD2 exomes AF: 0.0106 AC: 1652 AN: 155332 AF XY: 0.00821

Gnomad AFR exome AF: 0.000985

Gnomad AMR exome AF: 0.0633

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000164

Gnomad OTH exome AF: 0.00878

GnomAD4 exome AF: 0.00165 AC: 2309 AN: 1397740 Hom.: 73 Cov.: 33 AF XY: 0.00144 AC XY: 993 AN XY: 690330

African (AFR) AF: 0.000660 AC: 21 AN: 31828

American (AMR) AF: 0.0588 AC: 2145 AN: 36494

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25204

East Asian (EAS) AF: 0.00 AC: 0 AN: 36082

South Asian (SAS) AF: 0.00 AC: 0 AN: 79578

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43126

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5708

European-Non Finnish (NFE) AF: 0.0000139 AC: 15 AN: 1081604

Other (OTH) AF: 0.00220 AC: 128 AN: 58116

GnomAD4 genome AF: 0.00403 AC: 613 AN: 152248 Hom.: 15 Cov.: 32 AF XY: 0.00426 AC XY: 317 AN XY: 74436

African (AFR) AF: 0.00128 AC: 53 AN: 41538

American (AMR) AF: 0.0356 AC: 544 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 67996

Other (OTH) AF: 0.00522 AC: 11 AN: 2106

Alfa AF: 0.00130 Hom.: 4

Bravo AF: 0.00719

ESP6500AA AF: 0.000919 AC: 4

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.00355 AC: 396

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T
Eigen	Benign	0.0059
Eigen_PC	Benign	0.031
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.39
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.085
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.030	D
Polyphen		0.94	P
Vest4		0.26
MPC		0.56
ClinPred		0.022	T
GERP RS		4.9
PromoterAI		0.0076	Neutral
Varity_R		0.25
gMVP		0.28
Mutation Taster		=78/22	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: rs189368660; hg19: chr19-7697712;