11-67432813-G-A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_003952.3(RPS6KB2):​c.592G>A​(p.Glu198Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,614,014 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

RPS6KB2
NM_003952.3 missense

Scores

9
7
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.54
Variant links:
Genes affected
RPS6KB2 (HGNC:10437): (ribosomal protein S6 kinase B2) This gene encodes a member of the RSK (ribosomal S6 kinase) family of serine/threonine kinases. This kinase contains a kinase catalytic domain and phosphorylates the S6 ribosomal protein and eukaryotic translation initiation factor 4B (eIF4B). Phosphorylation of S6 leads to an increase in protein synthesis and cell proliferation. [provided by RefSeq, Jan 2015]
RPS6KB2-AS1 (HGNC:53744): (RPS6KB2 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2
High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RPS6KB2NM_003952.3 linkc.592G>A p.Glu198Lys missense_variant Exon 7 of 15 ENST00000312629.10 NP_003943.2 Q9UBS0-1
RPS6KB2XM_047427395.1 linkc.592G>A p.Glu198Lys missense_variant Exon 7 of 11 XP_047283351.1
RPS6KB2XM_047427396.1 linkc.592G>A p.Glu198Lys missense_variant Exon 7 of 10 XP_047283352.1
RPS6KB2XM_006718656.4 linkc.-9G>A 5_prime_UTR_variant Exon 3 of 11 XP_006718719.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RPS6KB2ENST00000312629.10 linkc.592G>A p.Glu198Lys missense_variant Exon 7 of 15 1 NM_003952.3 ENSP00000308413.5 Q9UBS0-1

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152180
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000654
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000321
AC:
8
AN:
249278
AF XY:
0.0000222
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000232
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:
0.00
GnomAD4 exome
AF:
0.0000178
AC:
26
AN:
1461716
Hom.:
0
Cov.:
32
AF XY:
0.0000138
AC XY:
10
AN XY:
727142
show subpopulations
Gnomad4 AFR exome
AF:
0.00
AC:
0
AN:
33480
Gnomad4 AMR exome
AF:
0.000425
AC:
19
AN:
44722
Gnomad4 ASJ exome
AF:
0.00
AC:
0
AN:
26136
Gnomad4 EAS exome
AF:
0.00
AC:
0
AN:
39698
Gnomad4 SAS exome
AF:
0.00
AC:
0
AN:
86256
Gnomad4 FIN exome
AF:
0.00
AC:
0
AN:
53294
Gnomad4 NFE exome
AF:
0.00000270
AC:
3
AN:
1111974
Gnomad4 Remaining exome
AF:
0.0000662
AC:
4
AN:
60388
Heterozygous variant carriers
0
2
4
6
8
10
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Variant carriers
0
2
4
6
8
10
<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
AF:
0.0000722
AC:
11
AN:
152298
Hom.:
0
Cov.:
33
AF XY:
0.0000671
AC XY:
5
AN XY:
74474
show subpopulations
Gnomad4 AFR
AF:
0.00
AC:
0
AN:
0
Gnomad4 AMR
AF:
0.000654
AC:
0.000653595
AN:
0.000653595
Gnomad4 ASJ
AF:
0.00
AC:
0
AN:
0
Gnomad4 EAS
AF:
0.00
AC:
0
AN:
0
Gnomad4 SAS
AF:
0.00
AC:
0
AN:
0
Gnomad4 FIN
AF:
0.00
AC:
0
AN:
0
Gnomad4 NFE
AF:
0.0000147
AC:
0.000014699
AN:
0.000014699
Gnomad4 OTH
AF:
0.00
AC:
0
AN:
0
Heterozygous variant carriers
0
1
2
3
4
5
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.0000250
Hom.:
0
Bravo
AF:
0.000178
ExAC
AF:
0.0000248
AC:
3

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Aug 15, 2024
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.592G>A (p.E198K) alteration is located in exon 7 (coding exon 7) of the RPS6KB2 gene. This alteration results from a G to A substitution at nucleotide position 592, causing the glutamic acid (E) at amino acid position 198 to be replaced by a lysine (K). 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
0.97
BayesDel_addAF
Uncertain
0.089
D
BayesDel_noAF
Pathogenic
0.16
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.43
T
Eigen
Pathogenic
0.79
Eigen_PC
Pathogenic
0.78
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.91
D
M_CAP
Benign
0.076
D
MetaRNN
Uncertain
0.69
D
MetaSVM
Benign
-0.58
T
MutationAssessor
Uncertain
2.9
M
PrimateAI
Pathogenic
0.85
D
PROVEAN
Uncertain
-3.8
D
REVEL
Pathogenic
0.70
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.0020
D
Polyphen
0.97
D
Vest4
0.95
MVP
0.77
MPC
0.27
ClinPred
0.91
D
GERP RS
5.3
Varity_R
0.96
gMVP
0.85
Mutation Taster
=42/58
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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs187592167; hg19: chr11-67200284; API