17-59945514-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_003161.4(RPS6KB1):c.1336G>C(p.Val446Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000159 in 1,569,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

RPS6KB1
NM_003161.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.28

Publications

1 publications found

Variant links:

Genes affected

RPS6KB1 (HGNC:10436): (ribosomal protein S6 kinase B1) This gene encodes a member of the ribosomal S6 kinase family of serine/threonine kinases. The encoded protein responds to mTOR (mammalian target of rapamycin) signaling to promote protein synthesis, cell growth, and cell proliferation. Activity of this gene has been associated with human cancer. Alternatively spliced transcript variants have been observed. The use of alternative translation start sites results in isoforms with longer or shorter N-termini which may differ in their subcellular localizations. There are two pseudogenes for this gene on chromosome 17. [provided by RefSeq, Jan 2013]

RPS6KB1 Gene-Disease associations (from GenCC):

hypertrophic cardiomyopathy
Inheritance: AD Classification: MODERATE, LIMITED Submitted by: ClinGen, PanelApp Australia

RPS6KB1 links:

ENSG00000267318 (HGNC:):

ENSG00000267318 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.20283869).

BS2

High AC in GnomAdExome4 at 24 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003161.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RPS6KB1	NM_003161.4	MANE Select	c.1336G>C	p.Val446Leu	missense	Exon 14 of 15	NP_003152.1	P23443-1
RPS6KB1	NM_001272042.2		c.1267G>C	p.Val423Leu	missense	Exon 13 of 14	NP_001258971.1	P23443-5
RPS6KB1	NM_001272060.2		c.1267G>C	p.Val423Leu	missense	Exon 14 of 15	NP_001258989.1	P23443-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RPS6KB1	ENST00000225577.9	TSL:1 MANE Select	c.1336G>C	p.Val446Leu	missense	Exon 14 of 15	ENSP00000225577.4	P23443-1
RPS6KB1	ENST00000406116.7	TSL:1	c.1336G>C	p.Val446Leu	missense	Exon 14 of 15	ENSP00000384335.3	P23443-4
ENSG00000267318	ENST00000591035.1	TSL:3	c.145G>C	p.Val49Leu	missense	Exon 2 of 4	ENSP00000468280.1	K7ERJ3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000401

AC:

AN:

249636

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:

0.00000887

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000169

AC:

AN:

1417834

Hom.:

Cov.:

AF XY:

0.0000184

AC XY:

AN XY:

707678

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32574

American (AMR)

AF:

0.00

AC:

AN:

44620

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25840

East Asian (EAS)

AF:

0.00

AC:

AN:

39490

South Asian (SAS)

AF:

0.00

AC:

AN:

85206

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53322

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.0000224

AC:

AN:

1072272

Other (OTH)

AF:

0.00

AC:

AN:

58812

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

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

AF:

0.00000657

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41426

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.25

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.064

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.84

M_CAP

Benign

0.013

MetaRNN

Benign

0.18

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.67

PhyloP100

5.3

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.070

REVEL

Benign

0.059

Sift

Benign

0.37

Sift4G

Benign

0.67

Polyphen

0.0010

Vest4

0.18

MVP

0.73

MPC

1.0

ClinPred

0.44

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.098

gMVP

0.56

Mutation Taster

=67/33

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over