rs12199759

Variant names:

• chr6-166471277-A-G
• rs12199759
• NM_021135.6:c.908-1372T>C

Variant summary

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

The NM_021135.6(RPS6KA2):​c.908-1372T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.182 in 152,166 control chromosomes in the GnomAD database, including 2,587 homozygotes. In-silico tool predicts 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 (2587 hom., cov: 33)
• Consequence: RPS6KA2 NM_021135.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.72
• Publications: 6 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.191 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPS6KA2	NM_021135.6	c.908-1372T>C		intron_variant	Intron 10 of 20	ENST00000265678.9	NP_066958.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPS6KA2	ENST00000265678.9	c.908-1372T>C		intron_variant	Intron 10 of 20	1	NM_021135.6	ENSP00000265678.4

Frequencies

GnomAD3 genomes AF: 0.182 AC: 27696 AN: 152048 Hom.: 2586 Cov.: 33

Gnomad AFR AF: 0.171

Gnomad AMI AF: 0.235

Gnomad AMR AF: 0.188

Gnomad ASJ AF: 0.146

Gnomad EAS AF: 0.0465

Gnomad SAS AF: 0.171

Gnomad FIN AF: 0.221

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.194

Gnomad OTH AF: 0.176

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.182 AC: 27701 AN: 152166 Hom.: 2587 Cov.: 33 AF XY: 0.181 AC XY: 13472 AN XY: 74382

African (AFR) AF: 0.171 AC: 7096 AN: 41506

American (AMR) AF: 0.188 AC: 2872 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.146 AC: 505 AN: 3468

East Asian (EAS) AF: 0.0466 AC: 241 AN: 5174

South Asian (SAS) AF: 0.172 AC: 829 AN: 4824

European-Finnish (FIN) AF: 0.221 AC: 2347 AN: 10598

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.194 AC: 13176 AN: 67972

Other (OTH) AF: 0.175 AC: 369 AN: 2114

Alfa AF: 0.187 Hom.: 5418

Bravo AF: 0.178

Asia WGS AF: 0.125 AC: 438 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.69
DANN	Benign	0.66
PhyloP100		-1.7
Mutation Taster		=100/0	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: rs12199759; hg19: chr6-166884765;