Genetic Variant RPS6KC1:p.Pro42Thr (chr1-213071024-C-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_012424.6(RPS6KC1):c.124C>A(p.Pro42Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00296 in 1,541,346 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0030 ( 7 hom. )

Consequence

RPS6KC1
NM_012424.6 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 5.08

Publications

11 publications found

Variant links:

COSMIC-nc: COSV104673822

Genes affected

RPS6KC1 (HGNC:10439): (ribosomal protein S6 kinase C1) Sphingosine kinase catalyzes the formation of sphingosine 1 phosphate, a lipid cellular messenger. The protein encoded by this gene can bind to sphingosine kinase and to phosphatidylinositol 3-phosphate, suggesting a role in sphingosine 1 phophate signaling. The encoded protein can also bind to peroxiredoxin-3 and may help transport it to mitochondria. [provided by RefSeq, Mar 2017]

RPS6KC1 Gene-Disease associations (from GenCC):

periventricular leukomalacia
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

RPS6KC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0115995705).

BP6

Variant 1-213071024-C-A is Benign according to our data. Variant chr1-213071024-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1159111.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012424.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RPS6KC1	NM_012424.6	MANE Select	c.124C>A	p.Pro42Thr	missense	Exon 2 of 15	NP_036556.2
RPS6KC1	NM_001349646.2		c.124C>A	p.Pro42Thr	missense	Exon 2 of 14	NP_001336575.1
RPS6KC1	NM_001349647.2		c.124C>A	p.Pro42Thr	missense	Exon 2 of 14	NP_001336576.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RPS6KC1	ENST00000366960.8	TSL:1 MANE Select	c.124C>A	p.Pro42Thr	missense	Exon 2 of 15	ENSP00000355927.3	Q96S38-1
RPS6KC1	ENST00000543354.5	TSL:1	c.-299C>A		5_prime_UTR	Exon 2 of 14	ENSP00000439282.2	F6RJM5
RPS6KC1	ENST00000614059.4	TSL:1	c.-498C>A		5_prime_UTR	Exon 2 of 15	ENSP00000483873.1	F5H7T0

Frequencies

GnomAD3 genomes

AF:

0.00243

AC:

370

AN:

152058

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000797

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00293

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00407

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00263

AC:

573

AN:

218054

AF XY:

0.00260

show subpopulations

Gnomad AFR exome

AF:

0.000642

Gnomad AMR exome

AF:

0.00133

Gnomad ASJ exome

AF:

0.000642

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00208

Gnomad NFE exome

AF:

0.00453

Gnomad OTH exome

AF:

0.00235

GnomAD4 exome

AF:

0.00302

AC:

4200

AN:

1389170

Hom.:

Cov.:

AF XY:

0.00291

AC XY:

2014

AN XY:

692878

show subpopulations

African (AFR)

AF:

0.000621

AC:

AN:

30596

American (AMR)

AF:

0.00145

AC:

AN:

37326

Ashkenazi Jewish (ASJ)

AF:

0.000595

AC:

AN:

25222

East Asian (EAS)

AF:

0.00

AC:

AN:

37000

South Asian (SAS)

AF:

0.00

AC:

AN:

78284

European-Finnish (FIN)

AF:

0.00220

AC:

116

AN:

52846

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5560

European-Non Finnish (NFE)

AF:

0.00360

AC:

3834

AN:

1064640

Other (OTH)

AF:

0.00281

AC:

162

AN:

57696

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.403

Heterozygous variant carriers

147

293

440

586

733

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

134

268

402

536

670

<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:

0.00243

AC:

370

AN:

152176

Hom.:

Cov.:

AF XY:

0.00230

AC XY:

171

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.000795

AC:

AN:

41524

American (AMR)

AF:

0.00131

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00293

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00407

AC:

277

AN:

67984

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

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:

0.00374

Hom.:

Bravo

AF:

0.00261

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00597

AC:

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.00256

AC:

ExAC

AF:

0.00287

AC:

348

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.27

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.041

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.57

MutationAssessor

Uncertain

2.7

PhyloP100

5.1

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-4.3

REVEL

Uncertain

0.30

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.56

MVP

0.64

MPC

0.21

ClinPred

0.036

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.52

gMVP

0.52

Mutation Taster

=31/69

disease causing

(source)

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

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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