11-67433341-C-T

Variant names:

• chr11-67433341-C-T
• rs55987642
• NM_003952.3:c.800C>T

Variant summary

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

The NM_003952.3(RPS6KB2):​c.800C>T​(p.Pro267Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0463 in 1,611,958 control chromosomes in the GnomAD database, including 1,980 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P267Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.036 (103 hom., cov: 33)
  • Exomes 𝑓: 0.047 (1877 hom.)
• Consequence: RPS6KB2 NM_003952.3 missense, splice_region
• Scores: Splicing: ADA: 0.006512
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.34
• Publications: 18 publications found

Genes affected

RPS6KB2 (HGNC:10437): (ribosomal protein S6 kinase B2) This gene encodes a member of the RSK (ribosomal S6 kinase) family of serine/threonine kinases. This kinase contains a kinase catalytic domain and phosphorylates the S6 ribosomal protein and eukaryotic translation initiation factor 4B (eIF4B). Phosphorylation of S6 leads to an increase in protein synthesis and cell proliferation. [provided by RefSeq, Jan 2015]

RPS6KB2-AS1 (HGNC:53744): (RPS6KB2 antisense RNA 1)

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.01272276).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0518 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003952.3. 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
	RPS6KB2	NM_003952.3	MANE Select	c.800C>T	p.Pro267Leu	missense splice_region	Exon 10 of 15	NP_003943.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS6KB2	ENST00000312629.10	TSL:1 MANE Select	c.800C>T	p.Pro267Leu	missense splice_region	Exon 10 of 15	ENSP00000308413.5
	RPS6KB2	ENST00000942409.1		c.800C>T	p.Pro267Leu	missense splice_region	Exon 10 of 15	ENSP00000612468.1
	RPS6KB2	ENST00000875118.1		c.806C>T	p.Pro269Leu	missense splice_region	Exon 10 of 15	ENSP00000545177.1

Frequencies

GnomAD3 genomes AF: 0.0364 AC: 5536 AN: 152142 Hom.: 103 Cov.: 33

Gnomad AFR AF: 0.00961

Gnomad AMI AF: 0.0471

Gnomad AMR AF: 0.0236

Gnomad ASJ AF: 0.0544

Gnomad EAS AF: 0.0566

Gnomad SAS AF: 0.0249

Gnomad FIN AF: 0.0403

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0532

Gnomad OTH AF: 0.0349

GnomAD2 exomes AF: 0.0421 AC: 10486 AN: 249268 AF XY: 0.0430

Gnomad AFR exome AF: 0.00866

Gnomad AMR exome AF: 0.0202

Gnomad ASJ exome AF: 0.0534

Gnomad EAS exome AF: 0.0613

Gnomad FIN exome AF: 0.0408

Gnomad NFE exome AF: 0.0538

Gnomad OTH exome AF: 0.0499

GnomAD4 exome AF: 0.0474 AC: 69181 AN: 1459698 Hom.: 1877 Cov.: 31 AF XY: 0.0469 AC XY: 34094 AN XY: 726364

African (AFR) AF: 0.00726 AC: 243 AN: 33476

American (AMR) AF: 0.0202 AC: 904 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0524 AC: 1369 AN: 26108

East Asian (EAS) AF: 0.0524 AC: 2080 AN: 39678

South Asian (SAS) AF: 0.0260 AC: 2241 AN: 86246

European-Finnish (FIN) AF: 0.0450 AC: 2395 AN: 53188

Middle Eastern (MID) AF: 0.0421 AC: 243 AN: 5766

European-Non Finnish (NFE) AF: 0.0515 AC: 57152 AN: 1110178

Other (OTH) AF: 0.0423 AC: 2554 AN: 60342

GnomAD4 genome AF: 0.0363 AC: 5533 AN: 152260 Hom.: 103 Cov.: 33 AF XY: 0.0344 AC XY: 2560 AN XY: 74434

African (AFR) AF: 0.00960 AC: 399 AN: 41546

American (AMR) AF: 0.0236 AC: 361 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0544 AC: 189 AN: 3472

East Asian (EAS) AF: 0.0563 AC: 291 AN: 5166

South Asian (SAS) AF: 0.0251 AC: 121 AN: 4822

European-Finnish (FIN) AF: 0.0403 AC: 428 AN: 10620

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0532 AC: 3621 AN: 68004

Other (OTH) AF: 0.0336 AC: 71 AN: 2114

Alfa AF: 0.0486 Hom.: 479

Bravo AF: 0.0361

TwinsUK AF: 0.0529 AC: 196

ALSPAC AF: 0.0529 AC: 204

ESP6500AA AF: 0.0117 AC: 46

ESP6500EA AF: 0.0537 AC: 443

ExAC AF: 0.0432 AC: 5218

Asia WGS AF: 0.0360 AC: 125 AN: 3478

EpiCase AF: 0.0526

EpiControl AF: 0.0524

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	25
DANN	Benign	0.95
DEOGEN2	Benign	0.40	T
Eigen	Benign	0.0082
Eigen_PC	Benign	0.018
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.91	L
PhyloP100		7.3
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-8.9	D
REVEL	Benign	0.27
Sift	Benign	0.63	T
Sift4G	Benign	0.33	T
Polyphen		1.0	D
Vest4		0.32
MPC		0.53
ClinPred		0.083	T
GERP RS		4.4
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.1
Varity_R		0.34
gMVP		0.73
Mutation Taster		=52/48	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0065
dbscSNV1_RF	Benign	0.028
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: rs55987642; hg19: chr11-67200812; COSMIC: COSV57049724; COSMIC: COSV57049724;