X-3612234-G-A

Variant names:

• chrX-3612234-G-A
• rs149966538
• NM_005044.5:c.1043C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_005044.5(PRKX):​c.1043C>T​(p.Pro348Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000331 in 1,206,900 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 11 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000090 (0 hom., 2 hem., cov: 22)
  • Exomes 𝑓: 0.000027 (0 hom. 9 hem.)
• Consequence: PRKX NM_005044.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.59
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.27028382).
• BS2: High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKX	NM_005044.5	c.1043C>T	p.Pro348Leu	missense_variant	Exon 8 of 9	ENST00000262848.6	NP_005035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKX	ENST00000262848.6	c.1043C>T	p.Pro348Leu	missense_variant	Exon 8 of 9	1	NM_005044.5	ENSP00000262848.5
PRKX	ENST00000462736.1	n.48C>T		non_coding_transcript_exon_variant	Exon 1 of 3	3
PRKX	ENST00000496648.1	n.22C>T		non_coding_transcript_exon_variant	Exon 1 of 2	3
PRKX	ENST00000425240.1	n.*76C>T		downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.0000902 AC: 10 AN: 110846 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000296

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000189

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000223 AC: 4 AN: 179464 AF XY: 0.0000312

Gnomad AFR exome AF: 0.000154

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000743

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000124

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000274 AC: 30 AN: 1096054 Hom.: 0 Cov.: 30 AF XY: 0.0000249 AC XY: 9 AN XY: 361534

African (AFR) AF: 0.000114 AC: 3 AN: 26315

American (AMR) AF: 0.00 AC: 0 AN: 34969

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19344

East Asian (EAS) AF: 0.000166 AC: 5 AN: 30080

South Asian (SAS) AF: 0.00 AC: 0 AN: 53640

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40466

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4128

European-Non Finnish (NFE) AF: 0.0000238 AC: 20 AN: 841103

Other (OTH) AF: 0.0000435 AC: 2 AN: 46009

GnomAD4 genome AF: 0.0000902 AC: 10 AN: 110846 Hom.: 0 Cov.: 22 AF XY: 0.0000605 AC XY: 2 AN XY: 33074

African (AFR) AF: 0.000296 AC: 9 AN: 30415

American (AMR) AF: 0.00 AC: 0 AN: 10281

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2645

East Asian (EAS) AF: 0.00 AC: 0 AN: 3533

South Asian (SAS) AF: 0.00 AC: 0 AN: 2628

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5916

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.0000189 AC: 1 AN: 53024

Other (OTH) AF: 0.00 AC: 0 AN: 1488

Alfa AF: 0.000142 Hom.: 1

Bravo AF: 0.000151

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1043C>T (p.P348L) alteration is located in exon 8 (coding exon 8) of the PRKX gene. This alteration results from a C to T substitution at nucleotide position 1043, causing the proline (P) at amino acid position 348 to be replaced by a leucine (L). 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	Benign	0.12
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	17
DANN	Benign	0.78
DEOGEN2	Benign	0.39	T
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.74	T
M_CAP	Uncertain	0.29	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.5	L
PhyloP100		7.6
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.27
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.043	D
Polyphen		0.35	B
Vest4		0.26
MVP		0.84
MPC		0.78
ClinPred		0.18	T
GERP RS		3.5
Varity_R		0.20
gMVP		0.47
Mutation Taster		=75/25	polymorphism

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: rs149966538; hg19: chrX-3530275; COSMIC: COSV99468798; COSMIC: COSV99468798;