chr5-109355935-G-A

Position:

• chr5-109355935-G-A

Variant summary

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

The NM_014819.5(PJA2):​c.1744C>T​(p.Arg582Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,460,980 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PJA2 NM_014819.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.52

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.1744C>T	p.Arg582Cys	missense_variant	7/10	ENST00000361189.7	NP_055634.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PJA2	ENST00000361189.7	c.1744C>T	p.Arg582Cys	missense_variant	7/10	1	NM_014819.5	ENSP00000354775.2
PJA2	ENST00000361557.4	c.1744C>T	p.Arg582Cys	missense_variant	6/9	2		ENSP00000355284.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460980 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726842

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

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

Feb 13, 2023

The c.1744C>T (p.R582C) alteration is located in exon 7 (coding exon 6) of the PJA2 gene. This alteration results from a C to T substitution at nucleotide position 1744, causing the arginine (R) at amino acid position 582 to be replaced by a cysteine (C). 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	0.99
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.41	T;T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	.;D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.49	T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.0	M;M
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-4.4	D;D
REVEL	Uncertain	0.30
Sift	Uncertain	0.011	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.52
MutPred		0.57		Loss of catalytic residue at M577 (P = 0.0056);Loss of catalytic residue at M577 (P = 0.0056);
MVP		0.39
MPC		2.5
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.43
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs748449108; hg19: chr5-108691636; COSMIC: COSV63274965;