rs779184447

Variant names:

• chr6-166430536-G-A
• rs779184447
• NM_021135.6:c.1498C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-166430536-G-A
• chr6-166430536-G-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_021135.6(RPS6KA2):​c.1498C>T​(p.Arg500Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,613,926 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R500Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: RPS6KA2 NM_021135.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.48
• Publications: 3 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 23 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021135.6. 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
	RPS6KA2	NM_021135.6	MANE Select	c.1498C>T	p.Arg500Trp	missense	Exon 16 of 21	NP_066958.2
	RPS6KA2	NM_001318936.2		c.1573C>T	p.Arg525Trp	missense	Exon 18 of 23	NP_001305865.2	F2Z2J1
	RPS6KA2	NM_001006932.3		c.1522C>T	p.Arg508Trp	missense	Exon 17 of 22	NP_001006933.3	Q15349-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS6KA2	ENST00000265678.9	TSL:1 MANE Select	c.1498C>T	p.Arg500Trp	missense	Exon 16 of 21	ENSP00000265678.4	Q15349-1
	RPS6KA2	ENST00000481261.6	TSL:1	c.1231C>T	p.Arg411Trp	missense	Exon 16 of 21	ENSP00000422484.1	B7Z3B5
	RPS6KA2	ENST00000510118.5	TSL:2	c.1573C>T	p.Arg525Trp	missense	Exon 18 of 23	ENSP00000422435.1	F2Z2J1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152116 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251172 AF XY: 0.00000737

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: 0.00000880

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1461810 Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15 AN XY: 727202

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1111982

Other (OTH) AF: 0.0000497 AC: 3 AN: 60392

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152116 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74306

African (AFR) AF: 0.0000241 AC: 1 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.0000193 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000247 AC: 3

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	Benign	0.13
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.14	N
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		1.5
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Benign	0.24
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.57
MVP		0.82
MPC		1.3
ClinPred		0.97	D
GERP RS		1.7
Varity_R		0.30
gMVP		0.35
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs779184447; hg19: chr6-166844024; COSMIC: COSV55822288;