11-67428568-A-G

Variant names:

• chr11-67428568-A-G
• rs1480887766
• NM_003952.3:c.23A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003952.3(RPS6KB2):​c.23A>G​(p.Asp8Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RPS6KB2 NM_003952.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.54

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPS6KB2	NM_003952.3	c.23A>G	p.Asp8Gly	missense_variant	Exon 1 of 15	ENST00000312629.10	NP_003943.2
RPS6KB2	XM_047427395.1	c.23A>G	p.Asp8Gly	missense_variant	Exon 1 of 11		XP_047283351.1
RPS6KB2	XM_047427396.1	c.23A>G	p.Asp8Gly	missense_variant	Exon 1 of 10		XP_047283352.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPS6KB2	ENST00000312629.10	c.23A>G	p.Asp8Gly	missense_variant	Exon 1 of 15	1	NM_003952.3	ENSP00000308413.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000427 AC: 1 AN: 234104 AF XY: 0.00

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: 0.00000978

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.23A>G (p.D8G) alteration is located in exon 1 (coding exon 1) of the RPS6KB2 gene. This alteration results from a A to G substitution at nucleotide position 23, causing the aspartic acid (D) at amino acid position 8 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	29
DANN	Benign	0.81
DEOGEN2	Benign	0.085	T;D
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.58	T;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Uncertain	0.49	T;T
MetaSVM	Uncertain	0.26	D
MutationAssessor	Benign	1.7	.;L
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-4.4	D;D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		0.99	.;D
Vest4		0.71
MutPred		0.18		Loss of stability (P = 0.0423);Loss of stability (P = 0.0423);
MVP		0.90
MPC		0.21
ClinPred		0.97	D
GERP RS		4.7
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.75
gMVP		0.56
Mutation Taster		=57/43	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

Publications

LitVar

Other links and lift over

dbSNP: rs1480887766; hg19: chr11-67196039; COSMIC: COSV105146721; COSMIC: COSV105146721;