19-7632458-G-T

Variant names:

• chr19-7632458-G-T
• NM_174895.3:c.226C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_174895.3(PCP2):​c.226C>A​(p.Arg76Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,672 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PCP2 NM_174895.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.755

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCP2	NM_174895.3	c.226C>A	p.Arg76Ser	missense_variant	Exon 3 of 4	ENST00000311069.6	NP_777555.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCP2	ENST00000311069.6	c.226C>A	p.Arg76Ser	missense_variant	Exon 3 of 4	1	NM_174895.3	ENSP00000310585.4
ENSG00000268400	ENST00000698368.1	n.114+1799G>T		intron_variant	Intron 2 of 19			ENSP00000513686.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461672 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727152

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	.;D
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Benign	0.57	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.010	T
MetaRNN	Uncertain	0.53	D;D
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.7	.;M
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-4.7	.;D
REVEL	Benign	0.18
Sift	Uncertain	0.027	.;D
Sift4G	Uncertain	0.011	D;D
Polyphen		0.68	.;P
Vest4		0.59
MutPred		0.45		.;Gain of phosphorylation at R76 (P = 0.0337);
MVP		0.29
MPC		0.52
ClinPred		0.97	D
GERP RS		3.8
Varity_R		0.48
gMVP		0.63

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-7697344;