Genetic Variant RPS6KC1:p.Pro42Ser (chr1-213071024-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_012424.6(RPS6KC1):c.124C>T(p.Pro42Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000072 in 1,389,664 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P42T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

RPS6KC1
NM_012424.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.08

Publications

11 publications found

Variant links:

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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>T	p.Pro42Ser	missense	Exon 2 of 15	NP_036556.2
RPS6KC1	NM_001349646.2		c.124C>T	p.Pro42Ser	missense	Exon 2 of 14	NP_001336575.1
RPS6KC1	NM_001349647.2		c.124C>T	p.Pro42Ser	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>T	p.Pro42Ser	missense	Exon 2 of 15	ENSP00000355927.3	Q96S38-1
RPS6KC1	ENST00000543354.5	TSL:1	c.-299C>T		5_prime_UTR	Exon 2 of 14	ENSP00000439282.2	F6RJM5
RPS6KC1	ENST00000614059.4	TSL:1	c.-498C>T		5_prime_UTR	Exon 2 of 15	ENSP00000483873.1	F5H7T0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

218054

AF XY:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.20e-7

AC:

AN:

1389664

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

693130

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30596

American (AMR)

AF:

0.00

AC:

AN:

37326

Ashkenazi Jewish (ASJ)

AF:

0.00

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:

0.00

AC:

AN:

52852

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5560

European-Non Finnish (NFE)

AF:

9.39e-7

AC:

AN:

1065124

Other (OTH)

AF:

0.00

AC:

AN:

57700

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Benign

-0.036

BayesDel_noAF

Benign

-0.29

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.036

MetaRNN

Uncertain

0.61

MetaSVM

Benign

-0.71

MutationAssessor

Uncertain

2.1

PhyloP100

5.1

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-4.2

REVEL

Benign

0.28

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.64

MutPred

0.35

Gain of phosphorylation at P42 (P = 0.0341)

MVP

0.60

MPC

0.38

ClinPred

0.99

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.40

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over