6-166419949-G-A

Variant names:

• chr6-166419949-G-A
• rs758524783
• NM_021135.6:c.1753C>T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_021135.6(RPS6KA2):​c.1753C>T​(p.Arg585Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,390 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: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: RPS6KA2 NM_021135.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.663

Genes affected

RPS6KA2 (HGNC:10431): (ribosomal protein S6 kinase A2) This gene encodes a member of the RSK (ribosomal S6 kinase) family of serine/threonine kinases. This kinase contains two non-identical kinase catalytic domains and phosphorylates various substrates, including members of the mitogen-activated kinase (MAPK) signalling pathway. The activity of this protein has been implicated in controlling cell growth and differentiation. Alternative splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jan 2016]

LOC124901460 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3058517).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPS6KA2	NM_021135.6	c.1753C>T	p.Arg585Cys	missense_variant	Exon 18 of 21	ENST00000265678.9	NP_066958.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPS6KA2	ENST00000265678.9	c.1753C>T	p.Arg585Cys	missense_variant	Exon 18 of 21	1	NM_021135.6	ENSP00000265678.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251358 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135858

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461390 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726990

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000189

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1777C>T (p.R593C) alteration is located in exon 19 (coding exon 19) of the RPS6KA2 gene. This alteration results from a C to T substitution at nucleotide position 1777, causing the arginine (R) at amino acid position 593 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T;T;.;.;.
Eigen	Benign	0.17
Eigen_PC	Benign	0.059
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.97	D;D;D;.;D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.31	T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.1	M;.;.;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.7	D;D;D;D;D
REVEL	Benign	0.26
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D;D
Polyphen		0.99	D;D;D;.;.
Vest4		0.37
MutPred		0.57		.;Loss of solvent accessibility (P = 0.0079);.;.;.;
MVP		0.66
MPC		0.75
ClinPred		0.98	D
GERP RS		2.3
Varity_R		0.43
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs758524783; hg19: chr6-166833437; COSMIC: COSV55829402;