19-7631728-AC-GT

Variant names:

• chr19-7631728-AC-GT
• NM_174895.3:c.371_372delGTinsAC
• PCP2 p.Arg124His

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_174895.3(PCP2):​c.371_372delGTinsAC​(p.Arg124His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R124C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PCP2 NM_174895.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.46
• Publications: 0 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, PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen
• 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: Uncertain_significance. The variant received 0 ACMG points.

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.371_372delGTinsAC	p.Arg124His	missense	N/A	NP_777555.1	Q8IVA1-1
	PET100	NM_001171155.2	MANE Select	c.*172_*173delACinsGT		3_prime_UTR	Exon 4 of 4	NP_001164626.1	P0DJ07
	PCP2	NM_001271830.2		c.323_324delGTinsAC	p.Arg108His	missense	N/A	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.371_372delGTinsAC	p.Arg124His	missense	N/A	ENSP00000310585.4	Q8IVA1-1
	PET100	ENST00000594797.6	TSL:1 MANE Select	c.*172_*173delACinsGT		3_prime_UTR	Exon 4 of 4	ENSP00000470539.1	P0DJ07
	ENSG00000268400	ENST00000698368.1		n.114+1069_114+1070delACinsGT		intron	N/A	ENSP00000513686.1	A0A8V8TM65

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr19-7696614;