chr1-213071037-A-G

Variant names:

• chr1-213071037-A-G
• rs775834541
• NM_012424.6:c.137A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_012424.6(RPS6KC1):​c.137A>G​(p.Gln46Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000217 in 1,385,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: RPS6KC1 NM_012424.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.95
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36061525).

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.137A>G	p.Gln46Arg	missense	Exon 2 of 15	NP_036556.2
	RPS6KC1	NM_001349646.2		c.137A>G	p.Gln46Arg	missense	Exon 2 of 14	NP_001336575.1
	RPS6KC1	NM_001349647.2		c.137A>G	p.Gln46Arg	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.137A>G	p.Gln46Arg	missense	Exon 2 of 15	ENSP00000355927.3	Q96S38-1
	RPS6KC1	ENST00000543354.5	TSL:1	c.-286A>G		5_prime_UTR	Exon 2 of 14	ENSP00000439282.2	F6RJM5
	RPS6KC1	ENST00000614059.4	TSL:1	c.-485A>G		5_prime_UTR	Exon 2 of 15	ENSP00000483873.1	F5H7T0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000918 AC: 2 AN: 217762 AF XY: 0.0000169

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000380

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000217 AC: 3 AN: 1385070 Hom.: 0 Cov.: 22 AF XY: 0.00000289 AC XY: 2 AN XY: 691198

African (AFR) AF: 0.00 AC: 0 AN: 30414

American (AMR) AF: 0.0000268 AC: 1 AN: 37318

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25124

East Asian (EAS) AF: 0.0000269 AC: 1 AN: 37114

South Asian (SAS) AF: 0.00 AC: 0 AN: 78338

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52872

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5526

European-Non Finnish (NFE) AF: 9.43e-7 AC: 1 AN: 1060804

Other (OTH) AF: 0.00 AC: 0 AN: 57560

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.011	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.19	N
PhyloP100		8.0
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.24
Sift	Benign	0.064	T
Sift4G	Uncertain	0.049	D
Polyphen		1.0	D
Vest4		0.49
MVP		0.52
MPC		0.15
ClinPred		0.58	D
GERP RS		5.4
Varity_R		0.30
gMVP		0.62
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs775834541; hg19: chr1-213244379;