chr11-67433348-C-A

Variant names:

• chr11-67433348-C-A
• rs4930427
• NM_003952.3:c.807C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_003952.3(RPS6KB2):​c.807C>A​(p.Phe269Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RPS6KB2 NM_003952.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0700
• Publications: 29 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS6KB2	NM_003952.3	MANE Select	c.807C>A	p.Phe269Leu	missense	Exon 10 of 15	NP_003943.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS6KB2	ENST00000312629.10	TSL:1 MANE Select	c.807C>A	p.Phe269Leu	missense	Exon 10 of 15	ENSP00000308413.5
	RPS6KB2	ENST00000525088.5	TSL:2	n.4220C>A		non_coding_transcript_exon	Exon 5 of 8
	RPS6KB2	ENST00000525996.7	TSL:5	n.*142C>A		non_coding_transcript_exon	Exon 6 of 11	ENSP00000473485.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Benign	0.0045	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	0.038
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.094	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		-0.070
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.66
MutPred		0.89		Gain of glycosylation at P267 (P = 0.1179)
MVP		0.56
MPC		0.54
ClinPred		1.0	D
GERP RS		0.60
Varity_R		0.92
gMVP		0.87
Mutation Taster		=44/56	disease causing

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: rs4930427; hg19: chr11-67200819;