19-7633434-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0410

Publications

14 publications found

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 Gene-Disease associations (from GenCC):

familial hemophagocytic lymphohistiocytosis 5
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
hereditary hemophagocytic lymphohistiocytosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
microvillus inclusion disease
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

STXBP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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
PCP2	NM_174895.3 link	c.24G>A	p.Thr8Thr	synonymous_variant	Exon 1 of 4	ENST00000311069.6	NP_777555.1
PCP2	XM_024451346.2 link	c.187G>A	p.Gly63Arg	missense_variant	Exon 1 of 5		XP_024307114.1
STXBP2	NM_001414484.1 link	c.-60+2588C>T		intron_variant	Intron 3 of 20		NP_001401413.1
PCP2	XM_006722639.4 link	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 link	c.24G>A	p.Thr8Thr	synonymous_variant	Exon 1 of 4	1	NM_174895.3	ENSP00000310585.4
ENSG00000268400	ENST00000698368.1 link	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.:

show subpopulations

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

GnomAD2 exomes

AF:

0.297

AC:

55860

AN:

187902

AF XY:

0.304

show subpopulations

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 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.:

AF XY:

0.345

AC XY:

243371

AN XY:

704550

show subpopulations

African (AFR)

AF:

0.156

AC:

5143

AN:

32890

American (AMR)

AF:

0.197

AC:

7740

AN:

39206

Ashkenazi Jewish (ASJ)

AF:

0.266

AC:

6755

AN:

25386

East Asian (EAS)

AF:

0.190

AC:

7280

AN:

38268

South Asian (SAS)

AF:

0.288

AC:

23401

AN:

81240

European-Finnish (FIN)

AF:

0.408

AC:

20686

AN:

50678

Middle Eastern (MID)

AF:

0.291

AC:

1661

AN:

5712

European-Non Finnish (NFE)

AF:

0.367

AC:

400926

AN:

1091348

Other (OTH)

AF:

0.327

AC:

19236

AN:

58896

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

16024

32047

48071

64094

80118

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12586

25172

37758

50344

62930

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.290

AC:

44059

AN:

151840

Hom.:

7063

Cov.:

AF XY:

0.290

AC XY:

21564

AN XY:

74236

show subpopulations

African (AFR)

AF:

0.164

AC:

6772

AN:

41388

American (AMR)

AF:

0.245

AC:

3746

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.270

AC:

936

AN:

3464

East Asian (EAS)

AF:

0.195

AC:

1006

AN:

5150

South Asian (SAS)

AF:

0.290

AC:

1396

AN:

4814

European-Finnish (FIN)

AF:

0.417

AC:

4411

AN:

10568

Middle Eastern (MID)

AF:

0.296

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.367

AC:

24879

AN:

67872

Other (OTH)

AF:

0.302

AC:

636

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1566

3131

4697

6262

7828

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

460

920

1380

1840

2300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.331

Hom.:

17195

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

LINK: link

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

(source)

DANN

Benign

0.61

PhyloP100

0.041

PromoterAI

-0.0080

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over