6-166432462-G-A

Variant names:

• chr6-166432462-G-A
• rs780204450
• NM_021135.6:c.1361C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BS2

The NM_021135.6(RPS6KA2):​c.1361C>T​(p.Ser454Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,856 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: RPS6KA2 NM_021135.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.22

Genes affected

RPS6KA2 (HGNC:10431): (ribosomal protein S6 kinase A2) This gene encodes a member of the RSK (ribosomal S6 kinase) family of serine/threonine kinases. This kinase contains two non-identical kinase catalytic domains and phosphorylates various substrates, including members of the mitogen-activated kinase (MAPK) signalling pathway. The activity of this protein has been implicated in controlling cell growth and differentiation. Alternative splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPS6KA2	NM_021135.6	c.1361C>T	p.Ser454Leu	missense_variant	Exon 15 of 21	ENST00000265678.9	NP_066958.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPS6KA2	ENST00000265678.9	c.1361C>T	p.Ser454Leu	missense_variant	Exon 15 of 21	1	NM_021135.6	ENSP00000265678.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251152 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135708

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460856 Hom.: 0 Cov.: 29 AF XY: 0.00000275 AC XY: 2 AN XY: 726804

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1385C>T (p.S462L) alteration is located in exon 16 (coding exon 16) of the RPS6KA2 gene. This alteration results from a C to T substitution at nucleotide position 1385, causing the serine (S) at amino acid position 462 to be replaced by a leucine (L). 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	Benign	0.089
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T;T;.;.;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D;.;D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.43	T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.55	N;.;.;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.1	D;D;D;D;D
REVEL	Benign	0.28
Sift	Uncertain	0.015	D;D;D;D;D
Sift4G	Uncertain	0.027	D;D;D;D;D
Polyphen		0.77	P;P;P;.;.
Vest4		0.57
MutPred		0.54		.;Loss of phosphorylation at S479 (P = 0.0064);.;.;.;
MVP		0.72
MPC		0.55
ClinPred		0.89	D
GERP RS		4.8
Varity_R		0.31
gMVP		0.45

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: rs780204450; hg19: chr6-166845950; COSMIC: COSV55825022;