dbSNP rs55987642: RPS6KB2:p.Pro267Gln (chr11-67433341-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_003952.3(RPS6KB2):c.800C>A(p.Pro267Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 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: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RPS6KB2
NM_003952.3 missense, splice_region

Scores

Splicing: ADA: 0.3209

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: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.893

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
RPS6KB2	NM_003952.3 link	c.800C>A	p.Pro267Gln	missense_variant, splice_region_variant	Exon 10 of 15	ENST00000312629.10	NP_003943.2
RPS6KB2	XM_047427395.1 link	c.778C>A	p.Arg260Ser	missense_variant, splice_region_variant	Exon 10 of 11		XP_047283351.1
RPS6KB2	XM_006718656.4 link	c.200C>A	p.Pro67Gln	missense_variant, splice_region_variant	Exon 6 of 11		XP_006718719.1
RPS6KB2	XM_047427396.1 link	c.709C>A	p.Arg237Ser	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>A	p.Pro267Gln	missense_variant, splice_region_variant	Exon 10 of 15	1	NM_003952.3	ENSP00000308413.5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000401

AC:

AN:

249268

AF XY:

0.00

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:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461080

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726932

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53196

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111486

Other (OTH)

AF:

0.00

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

479

ExAC

AF:

0.00000827

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Benign

0.0032

BayesDel_noAF

Benign

-0.23

CADD

Pathogenic

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.41

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.074

MetaRNN

Pathogenic

0.89

MetaSVM

Benign

-0.71

MutationAssessor

Uncertain

2.2

PhyloP100

7.3

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-7.1

REVEL

Uncertain

0.35

Sift

Benign

0.063

Sift4G

Uncertain

0.019

Polyphen

1.0

Vest4

0.81

MutPred

0.58

Loss of glycosylation at P267 (P = 0.0418);

MVP

0.83

MPC

0.51

ClinPred

0.87

GERP RS

4.4

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.1

Varity_R

0.64

gMVP

0.73

Mutation Taster

=49/51

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.32

dbscSNV1_RF

Benign

0.35

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.99

Position offset: 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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over