chr6-166432418-T-C

Variant names:

• chr6-166432418-T-C
• rs75225867
• NM_021135.6:c.1405A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_021135.6(RPS6KA2):​c.1405A>G​(p.Ile469Val) variant causes a missense change. The variant allele was found at a frequency of 0.00018 in 1,612,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: RPS6KA2 NM_021135.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.59
• Publications: 4 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20108789).
• BS2: High AC in GnomAd4 at 20 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.1405A>G	p.Ile469Val	missense	Exon 15 of 21	NP_066958.2
	RPS6KA2	NM_001318936.2		c.1480A>G	p.Ile494Val	missense	Exon 17 of 23	NP_001305865.2	F2Z2J1
	RPS6KA2	NM_001006932.3		c.1429A>G	p.Ile477Val	missense	Exon 16 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.1405A>G	p.Ile469Val	missense	Exon 15 of 21	ENSP00000265678.4	Q15349-1
	RPS6KA2	ENST00000481261.6	TSL:1	c.1138A>G	p.Ile380Val	missense	Exon 15 of 21	ENSP00000422484.1	B7Z3B5
	RPS6KA2	ENST00000510118.5	TSL:2	c.1480A>G	p.Ile494Val	missense	Exon 17 of 23	ENSP00000422435.1	F2Z2J1

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

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: 0.000250

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000120 AC: 30 AN: 250936 AF XY: 0.000118

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000247

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000185 AC: 270 AN: 1460338 Hom.: 0 Cov.: 29 AF XY: 0.000190 AC XY: 138 AN XY: 726584

African (AFR) AF: 0.00 AC: 0 AN: 33436

American (AMR) AF: 0.0000447 AC: 2 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

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

European-Non Finnish (NFE) AF: 0.000233 AC: 259 AN: 1110708

Other (OTH) AF: 0.000149 AC: 9 AN: 60336

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74482

African (AFR) AF: 0.0000721 AC: 3 AN: 41584

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.000235 Hom.: 0

Bravo AF: 0.000136

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000140 AC: 17

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

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	0.10
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.060	T
Eigen	Benign	-0.081
Eigen_PC	Benign	0.077
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.52	N
PhyloP100		4.6
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.086
Sift	Benign	0.19	T
Sift4G	Benign	0.21	T
Polyphen		0.0010	B
Vest4		0.31
MVP		0.74
MPC		0.54
ClinPred		0.14	T
GERP RS		4.6
Varity_R		0.13
gMVP		0.26
Mutation Taster		=67/33	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: rs75225867; hg19: chr6-166845906;