chr19-7632826-C-A

Position:

• chr19-7632826-C-A

Variant summary

Our verdict is Benign. Variant got -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. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCP2	NM_174895.3	c.56G>T	p.Gly19Val	missense_variant	2/4	ENST00000311069.6	NP_777555.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCP2	ENST00000311069.6	c.56G>T	p.Gly19Val	missense_variant	2/4	1	NM_174895.3	ENSP00000310585.4
ENSG00000268400	ENST00000698368.1	n.114+2167C>A		intron_variant				ENSP00000513686.1

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

GnomAD3 exomes AF: 0.0106 AC: 1652 AN: 155332 Hom.: 54 AF XY: 0.00821 AC XY: 679 AN XY: 82672

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 SAS 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

Gnomad4 AFR exome AF: 0.000660

Gnomad4 AMR exome AF: 0.0588

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000139

Gnomad4 OTH exome AF: 0.00220

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

Gnomad4 AFR AF: 0.00128

Gnomad4 AMR AF: 0.0356

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00522

Alfa AF: 0.000609 Hom.: 2

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 26, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

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;T
MetaRNN	Benign	0.0021	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	.;M
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-2.0	.;N
REVEL	Benign	0.085
Sift	Uncertain	0.0020	.;D
Sift4G	Uncertain	0.030	D;D
Polyphen		0.94	.;P
Vest4		0.26
MPC		0.56
ClinPred		0.022	T
GERP RS		4.9
Varity_R		0.25
gMVP		0.28

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

Publications

LitVar

Other links and lift over

dbSNP: rs189368660; hg19: chr19-7697712;