17-59893333-C-T

Variant names:

• chr17-59893333-C-T
• rs775849346
• NM_003161.4:c.141+8C>T

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.141+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RPS6KB1 NM_003161.4 splice_region, intron
• Scores: Splicing: ADA: 0.03904
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.78
• Publications: 0 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: 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 (BayesDel_noAF=-0.38).

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.141+8C>T		splice_region intron	N/A	NP_003152.1	P23443-1
	RPS6KB1	NM_001272042.2		c.141+8C>T		splice_region intron	N/A	NP_001258971.1	P23443-5
	RPS6KB1	NM_001272060.2		c.72+8C>T		splice_region intron	N/A	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.141+8C>T		splice_region intron	N/A	ENSP00000225577.4	P23443-1
	RPS6KB1	ENST00000406116.7	TSL:1	c.141+8C>T		splice_region intron	N/A	ENSP00000384335.3	P23443-4
	RPS6KB1	ENST00000880476.1		c.141+8C>T		splice_region intron	N/A	ENSP00000550535.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 207006 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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Benign	0.93
PhyloP100		1.8
PromoterAI		-0.077	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.039
dbscSNV1_RF	Benign	0.17
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: rs775849346; hg19: chr17-57970694;