Genetic Variant PRKX:p.Asp342Asn (chrX-3612253-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_ModerateBP6_ModerateBS2

The NM_005044.5(PRKX):c.1024G>A(p.Asp342Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000828 in 1,208,449 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 21)

Exomes 𝑓: 0.0000082 ( 0 hom. 3 hem. )

Consequence

PRKX
NM_005044.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.66

Publications

0 publications found

Variant links:

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]

PRKX links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.076358825).

BP6

Variant X-3612253-C-T is Benign according to our data. Variant chrX-3612253-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2605343.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1024G>A	p.Asp342Asn	missense	Exon 8 of 9	NP_005035.1	P51817

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PRKX	ENST00000262848.6	TSL:1 MANE Select	c.1024G>A	p.Asp342Asn	missense	Exon 8 of 9	ENSP00000262848.5	P51817
PRKX	ENST00000910398.1		c.1024G>A	p.Asp342Asn	missense	Exon 8 of 9	ENSP00000580457.1
PRKX	ENST00000953311.1		c.1024G>A	p.Asp342Asn	missense	Exon 8 of 9	ENSP00000623370.1

Frequencies

GnomAD3 genomes

AF:

0.00000902

AC:

AN:

110894

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000165

AC:

AN:

181830

AF XY:

0.0000302

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000368

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000820

AC:

AN:

1097555

Hom.:

Cov.:

AF XY:

0.00000827

AC XY:

AN XY:

362931

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26379

American (AMR)

AF:

0.00

AC:

AN:

35143

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19372

East Asian (EAS)

AF:

0.00

AC:

AN:

30171

South Asian (SAS)

AF:

0.00

AC:

AN:

53973

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40513

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.0000107

AC:

AN:

841803

Other (OTH)

AF:

0.00

AC:

AN:

46065

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000902

AC:

AN:

110894

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33096

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30478

American (AMR)

AF:

0.00

AC:

AN:

10284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2637

East Asian (EAS)

AF:

0.00

AC:

AN:

3523

South Asian (SAS)

AF:

0.00

AC:

AN:

2631

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5895

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.0000189

AC:

AN:

53031

Other (OTH)

AF:

0.00

AC:

AN:

1492

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000412

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-1.0

CADD

Benign

4.9

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.24

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.85

M_CAP

Benign

0.025

MetaRNN

Benign

0.076

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.60

PhyloP100

2.7

PrimateAI

Benign

0.32

PROVEAN

Benign

0.020

REVEL

Benign

0.10

Sift

Benign

0.58

Sift4G

Benign

0.45

Polyphen

0.0

Vest4

0.10

MutPred

0.28

Loss of disorder (P = 0.2019)

MVP

0.29

MPC

0.72

ClinPred

0.027

GERP RS

2.3

Varity_R

0.046

gMVP

0.22

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over