chr19-7633409-C-T

Position:

chr19-7633409-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_174895.3(PCP2):c.49G>A(p.Glu17Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000178 in 1,569,194 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

PCP2
NM_174895.3 missense, splice_region

Scores

Splicing: ADA: 0.00002669

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.304

Variant links:

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]

PCP2 links:

ENSG00000268400 (HGNC:):

ENSG00000268400 links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.007730454).

BP6

Variant 19-7633409-C-T is Benign according to our data. Variant chr19-7633409-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3210423.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCP2	NM_174895.3 link	c.49G>A	p.Glu17Lys	missense_variant, splice_region_variant	1/4	ENST00000311069.6	NP_777555.1	Q8IVA1-1
PCP2	XM_024451346.2 link	c.212G>A	p.Arg71Gln	missense_variant, splice_region_variant	1/5		XP_024307114.1
STXBP2	NM_001414484.1 link	c.-60+2563C>T		intron_variant			NP_001401413.1
PCP2	XM_006722639.4 link	c.-60-579G>A		intron_variant			XP_006722702.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCP2	ENST00000311069.6 link	c.49G>A	p.Glu17Lys	missense_variant, splice_region_variant	1/4	1	NM_174895.3	ENSP00000310585.4		Q8IVA1-1
ENSG00000268400	ENST00000698368.1 link	n.114+2750C>T		intron_variant				ENSP00000513686.1		A0A8V8TM65

Frequencies

GnomAD3 genomes

AF:

0.0000660

AC:

AN:

151438

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000243

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000459

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:

0.0000148

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000392

AC:

AN:

178782

Hom.:

AF XY:

0.0000314

AC XY:

AN XY:

95454

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000147

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000410

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000420

GnomAD4 exome

AF:

0.0000127

AC:

AN:

1417634

Hom.:

Cov.:

AF XY:

0.00000998

AC XY:

AN XY:

701060

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000131

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000124

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000551

Gnomad4 OTH exome

AF:

0.000102

GnomAD4 genome

AF:

0.0000660

AC:

AN:

151560

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74110

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.000459

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000148

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.0000277

Hom.:

Bravo

AF:

0.000234

ExAC

AF:

0.0000336

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 28, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.72

CADD

Benign

2.5

DANN

Benign

0.62

DEOGEN2

Benign

0.040

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0072

LIST_S2

Benign

0.54

M_CAP

Benign

0.0021

MetaRNN

Benign

0.0077

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.69

PROVEAN

Benign

0.57

REVEL

Benign

0.013

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.039

MutPred

0.14

Gain of ubiquitination at E17 (P = 0.0029);

MVP

0.081

MPC

0.13

ClinPred

0.019

GERP RS

-5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Varity_R

0.032

gMVP

0.25

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000027

dbscSNV1_RF

Benign

0.0020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over