chr17-59893236-G-A

Variant names:

• chr17-59893236-G-A
• rs756132794
• NM_003161.4:c.52G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003161.4(RPS6KB1):​c.52G>A​(p.Asp18Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,484 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RPS6KB1 NM_003161.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.10
• Publications: 1 publications found

Genes affected

RPS6KB1 (HGNC:10436): (ribosomal protein S6 kinase B1) This gene encodes a member of the ribosomal S6 kinase family of serine/threonine kinases. The encoded protein responds to mTOR (mammalian target of rapamycin) signaling to promote protein synthesis, cell growth, and cell proliferation. Activity of this gene has been associated with human cancer. Alternatively spliced transcript variants have been observed. The use of alternative translation start sites results in isoforms with longer or shorter N-termini which may differ in their subcellular localizations. There are two pseudogenes for this gene on chromosome 17. [provided by RefSeq, Jan 2013]

RPS6KB1 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18854874).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003161.4. 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
	RPS6KB1	NM_003161.4	MANE Select	c.52G>A	p.Asp18Asn	missense	Exon 1 of 15	NP_003152.1	P23443-1
	RPS6KB1	NM_001272042.2		c.52G>A	p.Asp18Asn	missense	Exon 1 of 14	NP_001258971.1	P23443-5
	RPS6KB1	NM_001369669.1		c.52G>A	p.Asp18Asn	missense	Exon 1 of 14	NP_001356598.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS6KB1	ENST00000225577.9	TSL:1 MANE Select	c.52G>A	p.Asp18Asn	missense	Exon 1 of 15	ENSP00000225577.4	P23443-1
	RPS6KB1	ENST00000406116.7	TSL:1	c.52G>A	p.Asp18Asn	missense	Exon 1 of 15	ENSP00000384335.3	P23443-4
	RPS6KB1	ENST00000880476.1		c.52G>A	p.Asp18Asn	missense	Exon 1 of 15	ENSP00000550535.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000406 AC: 1 AN: 246166 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: 0.0000549

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460484 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726446

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44450

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26062

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39648

South Asian (SAS) AF: 0.00 AC: 0 AN: 85972

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53274

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111508

Other (OTH) AF: 0.00 AC: 0 AN: 60336

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.0010
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.34	N
PhyloP100		6.1
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.088
Sift	Benign	0.12	T
Sift4G	Benign	0.62	T
Polyphen		0.0040	B
Vest4		0.51
MutPred		0.13		Gain of MoRF binding (P = 0.0725)
MVP		0.64
MPC		0.26
ClinPred		0.48	T
GERP RS		4.1
PromoterAI		0.066	Neutral
Varity_R		0.11
gMVP		0.17
Mutation Taster		=90/10	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

Other links and lift over

dbSNP: rs756132794; hg19: chr17-57970597;