chr19-7633434-C-T

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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 -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCP2	NM_174895.3	c.24G>A	p.Thr8Thr	synonymous_variant	Exon 1 of 4	ENST00000311069.6	NP_777555.1
PCP2	XM_024451346.2	c.187G>A	p.Gly63Arg	missense_variant	Exon 1 of 5		XP_024307114.1
STXBP2	NM_001414484.1	c.-60+2588C>T		intron_variant	Intron 3 of 20		NP_001401413.1
PCP2	XM_006722639.4	c.-60-604G>A		intron_variant	Intron 1 of 3		XP_006722702.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCP2	ENST00000311069.6	c.24G>A	p.Thr8Thr	synonymous_variant	Exon 1 of 4	1	NM_174895.3	ENSP00000310585.4
ENSG00000268400	ENST00000698368.1	n.114+2775C>T		intron_variant	Intron 2 of 19			ENSP00000513686.1

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

GnomAD3 exomes AF: 0.297 AC: 55860 AN: 187902 Hom.: 8923 AF XY: 0.304 AC XY: 30620 AN XY: 100584

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 SAS exome AF: 0.288

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

Gnomad4 AFR exome AF: 0.156

Gnomad4 AMR exome AF: 0.197

Gnomad4 ASJ exome AF: 0.266

Gnomad4 EAS exome AF: 0.190

Gnomad4 SAS exome AF: 0.288

Gnomad4 FIN exome AF: 0.408

Gnomad4 NFE exome AF: 0.367

Gnomad4 OTH exome AF: 0.327

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

Gnomad4 AFR AF: 0.164

Gnomad4 AMR AF: 0.245

Gnomad4 ASJ AF: 0.270

Gnomad4 EAS AF: 0.195

Gnomad4 SAS AF: 0.290

Gnomad4 FIN AF: 0.417

Gnomad4 NFE AF: 0.367

Gnomad4 OTH AF: 0.302

Alfa AF: 0.328 Hom.: 4432

Bravo AF: 0.269

Asia WGS AF: 0.250 AC: 873 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	3.2
DANN	Benign	0.61

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: rs1862514; hg19: chr19-7698320; COSMIC: COSV55403018; COSMIC: COSV55403018;