chrX-3655354-C-T

Variant names:

• chrX-3655354-C-T
• rs778576832
• NM_005044.5:c.394G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PP3_Strong BS2

The NM_005044.5(PRKX):​c.394G>A​(p.Gly132Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000911 in 1,098,236 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G132G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000091 (0 hom. 3 hem.)
• Consequence: PRKX NM_005044.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.59
• Publications: 0 publications found

Genes affected

PRKX (HGNC:9441): (protein kinase cAMP-dependent X-linked catalytic subunit) This gene encodes a serine threonine protein kinase that has similarity to the catalytic subunit of cyclic AMP dependent protein kinases. The encoded protein is developmentally regulated and may be involved in renal epithelial morphogenesis. This protein may also be involved in macrophage and granulocyte maturation. Abnormal recombination between this gene and a related pseudogene on chromosome Y is a frequent cause of sex reversal disorder in XX males and XY females. Pseudogenes of this gene are found on chromosomes X, 15 and Y. [provided by RefSeq, Feb 2010]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• BS2: High Hemizygotes in GnomAdExome4 at 3 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005044.5. 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
	PRKX	NM_005044.5	MANE Select	c.394G>A	p.Gly132Ser	missense	Exon 3 of 9	NP_005035.1	P51817

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKX	ENST00000262848.6	TSL:1 MANE Select	c.394G>A	p.Gly132Ser	missense	Exon 3 of 9	ENSP00000262848.5	P51817
	PRKX	ENST00000910398.1		c.394G>A	p.Gly132Ser	missense	Exon 3 of 9	ENSP00000580457.1
	PRKX	ENST00000953311.1		c.394G>A	p.Gly132Ser	missense	Exon 3 of 9	ENSP00000623370.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000546 AC: 1 AN: 183085 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000911 AC: 10 AN: 1098236 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 3 AN XY: 363592

African (AFR) AF: 0.00 AC: 0 AN: 26403

American (AMR) AF: 0.00 AC: 0 AN: 35203

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54149

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40530

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.0000119 AC: 10 AN: 842126

Other (OTH) AF: 0.00 AC: 0 AN: 46096

GnomAD4 genome Cov.: 23

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.029	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		6.6
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Uncertain	0.39
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.92		Loss of catalytic residue at G132 (P = 0.1042)
MVP		0.48
MPC		1.7
ClinPred		0.95	D
GERP RS		3.5
Varity_R		0.92
gMVP		0.89
Mutation Taster		=24/76	disease causing

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

Other links and lift over

dbSNP: rs778576832; hg19: chrX-3573395;