Genetic Variant PSKH2:p.Arg114Leu (chr8-86064476-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_033126.3(PSKH2):c.341G>T(p.Arg114Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000821 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R114Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

PSKH2
NM_033126.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.71

Publications

3 publications found

Variant links:

Genes affected

PSKH2 (HGNC:18997): (protein serine kinase H2) Predicted to enable ATP binding activity; protein serine kinase activity; and protein serine/threonine kinase activity. Predicted to be involved in protein phosphorylation. [provided by Alliance of Genome Resources, Apr 2022]

PSKH2 links:

ATP6V0D2 (HGNC:18266): (ATPase H+ transporting V0 subunit d2) Predicted to enable proton transmembrane transporter activity. Predicted to be involved in vacuolar acidification and vacuolar transport. Located in apical plasma membrane. Part of vacuolar proton-transporting V-type ATPase complex. [provided by Alliance of Genome Resources, Apr 2022]

ATP6V0D2 Gene-Disease associations (from GenCC):

Ehlers-Danlos syndrome
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ATP6V0D2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.798

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033126.3. 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
	PSKH2	NM_033126.3	MANE Select	c.341G>T	p.Arg114Leu	missense	Exon 2 of 3	NP_149117.1	Q96QS6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PSKH2	ENST00000276616.3	TSL:1 MANE Select	c.341G>T	p.Arg114Leu	missense	Exon 2 of 3	ENSP00000276616.2	Q96QS6
ATP6V0D2	ENST00000521564.1	TSL:3	c.-262-1912C>A		intron	N/A	ENSP00000429731.1	E5RHJ7
PSKH2	ENST00000517981.5	TSL:3	n.324G>T		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000517

AC:

AN:

251426

AF XY:

0.0000515

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.000246

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112012

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000247

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.028

Eigen

Benign

0.19

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.80

MetaSVM

Benign

-0.52

MutationAssessor

Benign

0.54

PhyloP100

4.7

PrimateAI

Benign

0.32

PROVEAN

Pathogenic

-5.8

REVEL

Uncertain

0.39

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0030

Polyphen

0.95

Vest4

0.68

MutPred

0.53

Loss of MoRF binding (P = 0.0047)

MVP

0.80

MPC

0.44

ClinPred

0.75

GERP RS

4.7

Varity_R

0.55

gMVP

0.16

Mutation Taster

=79/21

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over