rs2078819191

Variant names:

• chr1-213071016-G-A
• rs2078819191
• NM_012424.6:c.116G>A

Variant summary

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

The NM_012424.6(RPS6KC1):​c.116G>A​(p.Arg39Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000718 in 1,391,822 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: RPS6KC1 NM_012424.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.52
• Publications: 0 publications found

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

ACMG classification

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS6KC1	NM_012424.6	MANE Select	c.116G>A	p.Arg39Gln	missense	Exon 2 of 15	NP_036556.2
	RPS6KC1	NM_001349646.2		c.116G>A	p.Arg39Gln	missense	Exon 2 of 14	NP_001336575.1
	RPS6KC1	NM_001349647.2		c.116G>A	p.Arg39Gln	missense	Exon 2 of 14	NP_001336576.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS6KC1	ENST00000366960.8	TSL:1 MANE Select	c.116G>A	p.Arg39Gln	missense	Exon 2 of 15	ENSP00000355927.3	Q96S38-1
	RPS6KC1	ENST00000543354.5	TSL:1	c.-307G>A		5_prime_UTR	Exon 2 of 14	ENSP00000439282.2	F6RJM5
	RPS6KC1	ENST00000614059.4	TSL:1	c.-506G>A		5_prime_UTR	Exon 2 of 15	ENSP00000483873.1	F5H7T0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.18e-7 AC: 1 AN: 1391822 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 694154

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

African (AFR) AF: 0.00 AC: 0 AN: 30654

American (AMR) AF: 0.00 AC: 0 AN: 37436

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25256

East Asian (EAS) AF: 0.00 AC: 0 AN: 37066

South Asian (SAS) AF: 0.00 AC: 0 AN: 78448

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 52860

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5572

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1066820

Other (OTH) AF: 0.00 AC: 0 AN: 57710

⚠️ 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.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.35
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.017	T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.7	L
PhyloP100		8.5
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.23
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.53
MutPred		0.39		Loss of MoRF binding (P = 0.025)
MVP		0.66
MPC		0.44
ClinPred		0.98	D
GERP RS		4.7
Varity_R		0.23
gMVP		0.46
Mutation Taster		=63/37	polymorphism

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

Other links and lift over

dbSNP: rs2078819191; hg19: chr1-213244358; COSMIC: COSV100874071; COSMIC: COSV100874071;