Genetic Variant RPS6KB2:p.Pro267Leu (chr11-67433341-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_003952.3(RPS6KB2):c.800C>T(p.Pro267Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0463 in 1,611,958 control chromosomes in the GnomAD database, including 1,980 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.036 ( 103 hom., cov: 33)

Exomes 𝑓: 0.047 ( 1877 hom. )

Consequence

RPS6KB2
NM_003952.3 missense, splice_region

Scores

Splicing: ADA: 0.006512

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.34

Publications

18 publications found

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 links:

RPS6KB2-AS1 (HGNC:53744): (RPS6KB2 antisense RNA 1)

RPS6KB2-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01272276).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0518 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
RPS6KB2	NM_003952.3 link	c.800C>T	p.Pro267Leu	missense_variant, splice_region_variant	Exon 10 of 15	ENST00000312629.10	NP_003943.2
RPS6KB2	XM_047427395.1 link	c.778C>T	p.Arg260Cys	missense_variant, splice_region_variant	Exon 10 of 11		XP_047283351.1
RPS6KB2	XM_006718656.4 link	c.200C>T	p.Pro67Leu	missense_variant, splice_region_variant	Exon 6 of 11		XP_006718719.1
RPS6KB2	XM_047427396.1 link	c.709C>T	p.Arg237Cys	missense_variant, splice_region_variant	Exon 9 of 10		XP_047283352.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPS6KB2	ENST00000312629.10 link	c.800C>T	p.Pro267Leu	missense_variant, splice_region_variant	Exon 10 of 15	1	NM_003952.3	ENSP00000308413.5

Frequencies

GnomAD3 genomes

AF:

0.0364

AC:

5536

AN:

152142

Hom.:

103

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00961

Gnomad AMI

AF:

0.0471

Gnomad AMR

AF:

0.0236

Gnomad ASJ

AF:

0.0544

Gnomad EAS

AF:

0.0566

Gnomad SAS

AF:

0.0249

Gnomad FIN

AF:

0.0403

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0532

Gnomad OTH

AF:

0.0349

GnomAD2 exomes

AF:

0.0421

AC:

10486

AN:

249268

AF XY:

0.0430

show subpopulations

Gnomad AFR exome

AF:

0.00866

Gnomad AMR exome

AF:

0.0202

Gnomad ASJ exome

AF:

0.0534

Gnomad EAS exome

AF:

0.0613

Gnomad FIN exome

AF:

0.0408

Gnomad NFE exome

AF:

0.0538

Gnomad OTH exome

AF:

0.0499

GnomAD4 exome

AF:

0.0474

AC:

69181

AN:

1459698

Hom.:

1877

Cov.:

AF XY:

0.0469

AC XY:

34094

AN XY:

726364

show subpopulations

African (AFR)

AF:

0.00726

AC:

243

AN:

33476

American (AMR)

AF:

0.0202

AC:

904

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0524

AC:

1369

AN:

26108

East Asian (EAS)

AF:

0.0524

AC:

2080

AN:

39678

South Asian (SAS)

AF:

0.0260

AC:

2241

AN:

86246

European-Finnish (FIN)

AF:

0.0450

AC:

2395

AN:

53188

Middle Eastern (MID)

AF:

0.0421

AC:

243

AN:

5766

European-Non Finnish (NFE)

AF:

0.0515

AC:

57152

AN:

1110178

Other (OTH)

AF:

0.0423

AC:

2554

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.443

Heterozygous variant carriers

2830

5660

8491

11321

14151

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2082

4164

6246

8328

10410

<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:

0.0363

AC:

5533

AN:

152260

Hom.:

103

Cov.:

AF XY:

0.0344

AC XY:

2560

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.00960

AC:

399

AN:

41546

American (AMR)

AF:

0.0236

AC:

361

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0544

AC:

189

AN:

3472

East Asian (EAS)

AF:

0.0563

AC:

291

AN:

5166

South Asian (SAS)

AF:

0.0251

AC:

121

AN:

4822

European-Finnish (FIN)

AF:

0.0403

AC:

428

AN:

10620

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0532

AC:

3621

AN:

68004

Other (OTH)

AF:

0.0336

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

279

557

836

1114

1393

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

198

264

330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0486

Hom.:

479

Bravo

AF:

0.0361

TwinsUK

AF:

0.0529

AC:

196

ALSPAC

AF:

0.0529

AC:

204

ESP6500AA

AF:

0.0117

AC:

ESP6500EA

AF:

0.0537

AC:

443

ExAC

AF:

0.0432

AC:

5218

Asia WGS

AF:

0.0360

AC:

125

AN:

3478

EpiCase

AF:

0.0526

EpiControl

AF:

0.0524

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.68

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.40

Eigen

Benign

0.0082

Eigen_PC

Benign

0.018

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.80

MetaRNN

Benign

0.013

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.91

PhyloP100

7.3

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-8.9

REVEL

Benign

0.27

Sift

Benign

0.63

Sift4G

Benign

0.33

Polyphen

1.0

Vest4

0.32

MPC

0.53

ClinPred

0.083

GERP RS

4.4

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.1

Varity_R

0.34

gMVP

0.73

Mutation Taster

=52/48

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0065

dbscSNV1_RF

Benign

0.028

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over