6-166413894-T-C

Position:

• chr6-166413894-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000265678.9(RPS6KA2):​c.1976A>G​(p.Gln659Arg) 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 benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RPS6KA2 ENST00000265678.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.05

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]

LOC124901460 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30346587).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPS6KA2	NM_021135.6	c.1976A>G	p.Gln659Arg	missense_variant	20/21	ENST00000265678.9	NP_066958.2
LOC124901460	XR_007059866.1	n.764+245T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPS6KA2	ENST00000265678.9	c.1976A>G	p.Gln659Arg	missense_variant	20/21	1	NM_021135.6	ENSP00000265678	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 2022

The c.2000A>G (p.Q667R) alteration is located in exon 21 (coding exon 21) of the RPS6KA2 gene. This alteration results from a A to G substitution at nucleotide position 2000, causing the glutamine (Q) at amino acid position 667 to be replaced by an arginine (R). 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	0.077
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.056	T;T;.;.;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.92	D;D;D;.;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.30	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.44	N;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.7	N;N;N;N;N
REVEL	Benign	0.069
Sift	Benign	0.30	T;T;T;T;T
Sift4G	Benign	0.57	T;T;T;T;T
Polyphen		0.0	B;B;B;.;.
Vest4		0.32
MutPred		0.40		.;Gain of MoRF binding (P = 0.0394);.;.;.;
MVP		0.69
MPC		0.58
ClinPred		0.52	D
GERP RS		3.8
Varity_R		0.12
gMVP		0.68

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-166827382;