19-7632415-C-A

Position:

• chr19-7632415-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_174895.3(PCP2):​c.269G>T​(p.Gly90Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PCP2 NM_174895.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.77

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.826

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCP2	NM_174895.3	c.269G>T	p.Gly90Val	missense_variant	3/4	ENST00000311069.6	NP_777555.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCP2	ENST00000311069.6	c.269G>T	p.Gly90Val	missense_variant	3/4	1	NM_174895.3	ENSP00000310585.4
ENSG00000268400	ENST00000698368.1	n.114+1756C>A		intron_variant				ENSP00000513686.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 01, 2024

The c.269G>T (p.G90V) alteration is located in exon 3 (coding exon 3) of the PCP2 gene. This alteration results from a G to T substitution at nucleotide position 269, causing the glycine (G) at amino acid position 90 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	.;D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.018	T
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	0.55	.;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-8.6	.;D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.93
MutPred		0.49		.;Gain of MoRF binding (P = 0.2321);
MVP		0.37
MPC		0.62
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.91
gMVP		0.51

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: rs2031352814; hg19: chr19-7697301;