rs56376112

Variant names:

• chr17-59893319-G-A
• rs56376112
• NM_003161.4:c.135G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003161.4(RPS6KB1):​c.135G>A​(p.Glu45Glu) variant causes a synonymous change. The variant allele was found at a frequency of 0.00138 in 1,607,990 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0076 (11 hom., cov: 32)
  • Exomes 𝑓: 0.00073 (12 hom.)
• Consequence: RPS6KB1 NM_003161.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.30
• Publications: 3 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: MODERATE, LIMITED Submitted by: ClinGen, PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 17-59893319-G-A is Benign according to our data. Variant chr17-59893319-G-A is described in ClinVar as Benign. ClinVar VariationId is 781310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00756 (1152/152328) while in subpopulation AFR AF = 0.0262 (1088/41562). AF 95% confidence interval is 0.0249. There are 11 homozygotes in GnomAd4. There are 532 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1152 AD gene.

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.135G>A	p.Glu45Glu	synonymous	Exon 1 of 15	NP_003152.1	P23443-1
	RPS6KB1	NM_001272042.2		c.135G>A	p.Glu45Glu	synonymous	Exon 1 of 14	NP_001258971.1	P23443-5
	RPS6KB1	NM_001272060.2		c.66G>A	p.Glu22Glu	synonymous	Exon 1 of 15	NP_001258989.1	P23443-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS6KB1	ENST00000225577.9	TSL:1 MANE Select	c.135G>A	p.Glu45Glu	synonymous	Exon 1 of 15	ENSP00000225577.4	P23443-1
	RPS6KB1	ENST00000406116.7	TSL:1	c.135G>A	p.Glu45Glu	synonymous	Exon 1 of 15	ENSP00000384335.3	P23443-4
	RPS6KB1	ENST00000880476.1		c.135G>A	p.Glu45Glu	synonymous	Exon 1 of 15	ENSP00000550535.1

Frequencies

GnomAD3 genomes AF: 0.00758 AC: 1153 AN: 152210 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0263

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00187 AC: 435 AN: 232282 AF XY: 0.00136

Gnomad AFR exome AF: 0.0276

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000482

Gnomad OTH exome AF: 0.000882

GnomAD4 exome AF: 0.000728 AC: 1059 AN: 1455662 Hom.: 12 Cov.: 31 AF XY: 0.000619 AC XY: 448 AN XY: 723622

African (AFR) AF: 0.0266 AC: 889 AN: 33364

American (AMR) AF: 0.00139 AC: 61 AN: 43736

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25962

East Asian (EAS) AF: 0.00 AC: 0 AN: 39458

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85324

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52626

Middle Eastern (MID) AF: 0.000523 AC: 3 AN: 5738

European-Non Finnish (NFE) AF: 0.00000721 AC: 8 AN: 1109374

Other (OTH) AF: 0.00161 AC: 97 AN: 60080

GnomAD4 genome AF: 0.00756 AC: 1152 AN: 152328 Hom.: 11 Cov.: 32 AF XY: 0.00714 AC XY: 532 AN XY: 74494

African (AFR) AF: 0.0262 AC: 1088 AN: 41562

American (AMR) AF: 0.00320 AC: 49 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00615 AC: 13 AN: 2114

Alfa AF: 0.00373 Hom.: 4

Bravo AF: 0.00862

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	14
DANN	Benign	0.96
PhyloP100		5.3
PromoterAI		-0.027	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Mutation Taster		=21/79	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: rs56376112; hg19: chr17-57970680; COSMIC: COSV56679900; COSMIC: COSV56679900;