11-67431465-A-G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_003952.3(RPS6KB2):​c.407A>G​(p.Tyr136Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,613,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

RPS6KB2
NM_003952.3 missense

Scores

8
6
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.89
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 -2 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.933
BS2
High AC in GnomAdExome4 at 36 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RPS6KB2NM_003952.3 linkc.407A>G p.Tyr136Cys missense_variant Exon 5 of 15 ENST00000312629.10 NP_003943.2 Q9UBS0-1
RPS6KB2XM_047427395.1 linkc.407A>G p.Tyr136Cys missense_variant Exon 5 of 11 XP_047283351.1
RPS6KB2XM_047427396.1 linkc.407A>G p.Tyr136Cys missense_variant Exon 5 of 10 XP_047283352.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RPS6KB2ENST00000312629.10 linkc.407A>G p.Tyr136Cys missense_variant Exon 5 of 15 1 NM_003952.3 ENSP00000308413.5 Q9UBS0-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152138
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000601
AC:
15
AN:
249532
AF XY:
0.0000591
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000376
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000883
Gnomad OTH exome
AF:
0.000165
GnomAD4 exome
AF:
0.0000246
AC:
36
AN:
1461834
Hom.:
0
Cov.:
31
AF XY:
0.0000248
AC XY:
18
AN XY:
727216
show subpopulations
Gnomad4 AFR exome
AF:
0.00
AC:
0
AN:
33480
Gnomad4 AMR exome
AF:
0.000313
AC:
14
AN:
44724
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:
0.0000187
AC:
1
AN:
53408
Gnomad4 NFE exome
AF:
0.0000135
AC:
15
AN:
1111970
Gnomad4 Remaining exome
AF:
0.0000993
AC:
6
AN:
60394
Heterozygous variant carriers
0
3
6
8
11
14
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:
0.0000197
AC:
3
AN:
152138
Hom.:
0
Cov.:
31
AF XY:
0.0000135
AC XY:
1
AN XY:
74314
show subpopulations
Gnomad4 AFR
AF:
0.0000241
AC:
0.0000241371
AN:
0.0000241371
Gnomad4 AMR
AF:
0.00
AC:
0
AN:
0
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:
0.0000294
AC:
0.000029404
AN:
0.000029404
Gnomad4 OTH
AF:
0.00
AC:
0
AN:
0
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000340
ExAC
AF:
0.0000660
AC:
8
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Apr 27, 2022
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.407A>G (p.Y136C) alteration is located in exon 5 (coding exon 5) of the RPS6KB2 gene. This alteration results from a A to G substitution at nucleotide position 407, causing the tyrosine (Y) at amino acid position 136 to be replaced by a cysteine (C). 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
Uncertain
0.42
BayesDel_addAF
Uncertain
0.019
T
BayesDel_noAF
Uncertain
0.11
CADD
Pathogenic
30
DANN
Uncertain
1.0
DEOGEN2
Benign
0.39
T
Eigen
Pathogenic
0.75
Eigen_PC
Pathogenic
0.77
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.89
D
M_CAP
Benign
0.056
D
MetaRNN
Pathogenic
0.93
D
MetaSVM
Benign
-0.31
T
MutationAssessor
Benign
1.1
L
PrimateAI
Pathogenic
0.84
D
PROVEAN
Pathogenic
-8.5
D
REVEL
Pathogenic
0.69
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.025
D
Polyphen
1.0
D
Vest4
0.92
MutPred
0.86
Loss of phosphorylation at Y136 (P = 0.1957);
MVP
0.68
MPC
0.55
ClinPred
0.86
D
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.90
gMVP
0.76
Mutation Taster
=35/65
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs747230226; hg19: chr11-67198936; COSMIC: COSV57048174; COSMIC: COSV57048174; API