19-7631792-C-T

Variant names:

• chr19-7631792-C-T
• rs112367781
• NM_174895.3:c.308G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_174895.3(PCP2):​c.308G>A​(p.Arg103Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 1,419,004 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0079 (12 hom., cov: 32)
  • Exomes 𝑓: 0.00090 (11 hom.)
• Consequence: PCP2 NM_174895.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.26
• Publications: 5 publications found

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]

PET100 (HGNC:40038): (PET100 cytochrome c oxidase chaperone) Mitochondrial complex IV, or cytochrome c oxidase, is a large transmembrane protein complex that is part of the respiratory electron transport chain of mitochondria. The small protein encoded by this gene plays a role in the biogenesis of mitochondrial complex IV. This protein localizes to the inner mitochondrial membrane and is exposed to the intermembrane space. Mutations in this gene are associated with mitochondrial complex IV deficiency. This gene has a pseudogene on chromosome 3. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2014]

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]

STXBP2 Gene-Disease associations (from GenCC):

• familial hemophagocytic lymphohistiocytosis 5

  Inheritance: AD, AR 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003402561).
• BP6: Variant 19-7631792-C-T is Benign according to our data. Variant chr19-7631792-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1188512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00789 (1200/152028) while in subpopulation AFR AF = 0.0273 (1132/41436). AF 95% confidence interval is 0.026. There are 12 homozygotes in GnomAd4. There are 561 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_174895.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCP2	NM_174895.3	MANE Select	c.308G>A	p.Arg103Gln	missense	Exon 4 of 4	NP_777555.1	Q8IVA1-1
	PET100	NM_001171155.2	MANE Select	c.*236C>T		3_prime_UTR	Exon 4 of 4	NP_001164626.1	P0DJ07
	PCP2	NM_001271830.2		c.260G>A	p.Arg87Gln	missense	Exon 4 of 4	NP_001258759.1	Q8IVA1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCP2	ENST00000311069.6	TSL:1 MANE Select	c.308G>A	p.Arg103Gln	missense	Exon 4 of 4	ENSP00000310585.4	Q8IVA1-1
	PET100	ENST00000594797.6	TSL:1 MANE Select	c.*236C>T		3_prime_UTR	Exon 4 of 4	ENSP00000470539.1	P0DJ07
	ENSG00000268400	ENST00000698368.1		n.114+1133C>T		intron	N/A	ENSP00000513686.1	A0A8V8TM65

Frequencies

GnomAD3 genomes AF: 0.00788 AC: 1197 AN: 151910 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0273

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00719

GnomAD2 exomes AF: 0.00273 AC: 373 AN: 136538 AF XY: 0.00200

Gnomad AFR exome AF: 0.0273

Gnomad AMR exome AF: 0.00247

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000156

Gnomad OTH exome AF: 0.00150

GnomAD4 exome AF: 0.000897 AC: 1136 AN: 1266976 Hom.: 11 Cov.: 32 AF XY: 0.000845 AC XY: 520 AN XY: 615330

African (AFR) AF: 0.0308 AC: 828 AN: 26926

American (AMR) AF: 0.00316 AC: 69 AN: 21856

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17590

East Asian (EAS) AF: 0.0000303 AC: 1 AN: 32996

South Asian (SAS) AF: 0.0000585 AC: 3 AN: 51286

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45886

Middle Eastern (MID) AF: 0.00270 AC: 13 AN: 4814

European-Non Finnish (NFE) AF: 0.000110 AC: 112 AN: 1014212

Other (OTH) AF: 0.00214 AC: 110 AN: 51410

GnomAD4 genome AF: 0.00789 AC: 1200 AN: 152028 Hom.: 12 Cov.: 32 AF XY: 0.00755 AC XY: 561 AN XY: 74312

African (AFR) AF: 0.0273 AC: 1132 AN: 41436

American (AMR) AF: 0.00288 AC: 44 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67976

Other (OTH) AF: 0.00712 AC: 15 AN: 2108

Alfa AF: 0.00348 Hom.: 13

Bravo AF: 0.00938

ESP6500AA AF: 0.0264 AC: 116

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00285 AC: 327

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.51
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.3
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.10
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.22	T
Polyphen		1.0	D
Vest4		0.21
MVP		0.20
MPC		0.59
ClinPred		0.020	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.12
gMVP		0.25
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs112367781; hg19: chr19-7696678; COSMIC: COSV60696998; COSMIC: COSV60696998;