chr5-109344285-T-C

Position:

• chr5-109344285-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014819.5(PJA2):​c.1906A>G​(p.Ile636Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PJA2 NM_014819.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.22

Genes affected

PJA2 (HGNC:17481): (praja ring finger ubiquitin ligase 2) Enables protein kinase A catalytic subunit binding activity; protein kinase A regulatory subunit binding activity; and ubiquitin-protein transferase activity. Involved in several processes, including protein ubiquitination; regulation of macrophage activation; and regulation of signal transduction. Located in cytoplasm; intermediate filament cytoskeleton; and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PJA2	NM_014819.5	c.1906A>G	p.Ile636Val	missense_variant	9/10	ENST00000361189.7	NP_055634.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PJA2	ENST00000361189.7	c.1906A>G	p.Ile636Val	missense_variant	9/10	1	NM_014819.5	ENSP00000354775.2
PJA2	ENST00000361557.4	c.1906A>G	p.Ile636Val	missense_variant	8/9	2		ENSP00000355284.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.000224 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 29, 2024

The c.1906A>G (p.I636V) alteration is located in exon 9 (coding exon 8) of the PJA2 gene. This alteration results from a A to G substitution at nucleotide position 1906, causing the isoleucine (I) at amino acid position 636 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.060	T;T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	.;D
M_CAP	Benign	0.025	D
MetaRNN	Uncertain	0.54	D;D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	1.0	L;L
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.63	N;N
REVEL	Uncertain	0.36
Sift	Benign	0.15	T;T
Sift4G	Benign	0.069	T;T
Polyphen		1.0	D;D
Vest4		0.50
MutPred		0.56		Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);
MVP		0.75
MPC		2.0
ClinPred		0.88	D
GERP RS		6.0
Varity_R		0.087
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1454354379; hg19: chr5-108679986;