rs2229712

Variant names:

• chr1-26557020-A-C
• rs2229712
• NM_002953.4:c.1004A>C

Your query was ambiguous. Multiple possible variants found:

• chr1-26557020-A-C
• chr1-26557020-A-G
• chr1-26557020-A-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002953.4(RPS6KA1):​c.1004A>C​(p.Lys335Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.217 in 1,613,156 control chromosomes in the GnomAD database, including 40,223 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.18 (3001 hom., cov: 32)
  • Exomes 𝑓: 0.22 (37222 hom.)
• Consequence: RPS6KA1 NM_002953.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.21
• Publications: 38 publications found

Genes affected

RPS6KA1 (HGNC:10430): (ribosomal protein S6 kinase A1) This gene encodes a member of the RSK (ribosomal S6 kinase) family of serine/threonine kinases. This kinase contains 2 nonidentical 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. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016505122).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.25 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPS6KA1	NM_002953.4	c.1004A>C	p.Lys335Thr	missense_variant	Exon 13 of 22	ENST00000374168.7	NP_002944.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPS6KA1	ENST00000374168.7	c.1004A>C	p.Lys335Thr	missense_variant	Exon 13 of 22	1	NM_002953.4	ENSP00000363283.2

Frequencies

GnomAD3 genomes AF: 0.177 AC: 26886 AN: 152080 Hom.: 2999 Cov.: 32

Gnomad AFR AF: 0.0404

Gnomad AMI AF: 0.273

Gnomad AMR AF: 0.257

Gnomad ASJ AF: 0.308

Gnomad EAS AF: 0.178

Gnomad SAS AF: 0.245

Gnomad FIN AF: 0.198

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.225

Gnomad OTH AF: 0.192

GnomAD2 exomes AF: 0.219 AC: 55162 AN: 251326 AF XY: 0.225

Gnomad AFR exome AF: 0.0405

Gnomad AMR exome AF: 0.288

Gnomad ASJ exome AF: 0.292

Gnomad EAS exome AF: 0.168

Gnomad FIN exome AF: 0.202

Gnomad NFE exome AF: 0.220

Gnomad OTH exome AF: 0.222

GnomAD4 exome AF: 0.221 AC: 322785 AN: 1460958 Hom.: 37222 Cov.: 33 AF XY: 0.223 AC XY: 162396 AN XY: 726802

African (AFR) AF: 0.0340 AC: 1139 AN: 33480

American (AMR) AF: 0.289 AC: 12925 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.293 AC: 7647 AN: 26122

East Asian (EAS) AF: 0.201 AC: 7963 AN: 39694

South Asian (SAS) AF: 0.258 AC: 22244 AN: 86244

European-Finnish (FIN) AF: 0.198 AC: 10579 AN: 53334

Middle Eastern (MID) AF: 0.223 AC: 1287 AN: 5768

European-Non Finnish (NFE) AF: 0.221 AC: 246081 AN: 1111230

Other (OTH) AF: 0.214 AC: 12920 AN: 60364

GnomAD4 genome AF: 0.177 AC: 26889 AN: 152198 Hom.: 3001 Cov.: 32 AF XY: 0.180 AC XY: 13399 AN XY: 74398

African (AFR) AF: 0.0403 AC: 1674 AN: 41540

American (AMR) AF: 0.257 AC: 3928 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.308 AC: 1071 AN: 3472

East Asian (EAS) AF: 0.179 AC: 924 AN: 5170

South Asian (SAS) AF: 0.245 AC: 1184 AN: 4824

European-Finnish (FIN) AF: 0.198 AC: 2099 AN: 10596

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.225 AC: 15307 AN: 67994

Other (OTH) AF: 0.191 AC: 405 AN: 2116

Alfa AF: 0.211 Hom.: 9561

Bravo AF: 0.174

TwinsUK AF: 0.226 AC: 837

ALSPAC AF: 0.216 AC: 834

ESP6500AA AF: 0.0474 AC: 209

ESP6500EA AF: 0.238 AC: 2051

ExAC AF: 0.212 AC: 25691

Asia WGS AF: 0.196 AC: 682 AN: 3478

EpiCase AF: 0.227

EpiControl AF: 0.221

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T;.;.;.;.
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.98	D
MetaRNN	Benign	0.0017	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.84	L;.;.;.;.
PhyloP100		7.2
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-2.1	N;N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.31	T;T;T;T;T
Sift4G	Benign	0.33	T;T;T;T;T
Polyphen		0.29	B;.;.;.;B
Vest4		0.26
MPC		0.74
ClinPred		0.039	T
GERP RS		5.5
PromoterAI		-0.0015	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.66
gMVP		0.66
Mutation Taster		=94/6	polymorphism (auto)

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: rs2229712; hg19: chr1-26883511; COSMIC: COSV64809850; COSMIC: COSV64809850;