NM_014496.5:c.2209A>G

Variant names:

• chrX-84064306-T-C
• rs376230365
• NM_014496.5:c.2209A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_014496.5(RPS6KA6):​c.2209A>G​(p.Met737Val) variant causes a missense change. The variant allele was found at a frequency of 0.000135 in 1,206,914 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 62 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., 6 hem., cov: 22)
  • Exomes 𝑓: 0.00014 (0 hom. 56 hem.)
• Consequence: RPS6KA6 NM_014496.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.63
• Publications: 1 publications found

Genes affected

RPS6KA6 (HGNC:10435): (ribosomal protein S6 kinase A6) This gene encodes a member of ribosomal S6 kinase family, serine-threonine protein kinases which are regulated by growth factors. The encoded protein may be distinct from other members of this family, however, as studies suggest it is not growth factor dependent and may not participate in the same signaling pathways. [provided by RefSeq, Jan 2010]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18496487).
• BS2: High Hemizygotes in GnomAd4 at 6 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014496.5. 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
	RPS6KA6	NM_014496.5	MANE Select	c.2209A>G	p.Met737Val	missense	Exon 22 of 22	NP_055311.1	Q9UK32-1
	RPS6KA6	NM_001330512.1		c.2209A>G	p.Met737Val	missense	Exon 24 of 24	NP_001317441.1	Q9UK32-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS6KA6	ENST00000262752.5	TSL:1 MANE Select	c.2209A>G	p.Met737Val	missense	Exon 22 of 22	ENSP00000262752.2	Q9UK32-1
	RPS6KA6	ENST00000620340.4	TSL:5	c.2209A>G	p.Met737Val	missense	Exon 22 of 22	ENSP00000483896.1	Q9UK32-2
	RPS6KA6	ENST00000911420.1		c.2170A>G	p.Met724Val	missense	Exon 22 of 22	ENSP00000581479.1

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 14 AN: 111605 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000244

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000137 AC: 24 AN: 175681 AF XY: 0.0000659

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: 0.000129

Gnomad NFE exome AF: 0.000284

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000136 AC: 149 AN: 1095309 Hom.: 0 Cov.: 29 AF XY: 0.000155 AC XY: 56 AN XY: 360887

African (AFR) AF: 0.00 AC: 0 AN: 26354

American (AMR) AF: 0.00 AC: 0 AN: 35017

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19338

East Asian (EAS) AF: 0.00 AC: 0 AN: 30139

South Asian (SAS) AF: 0.00 AC: 0 AN: 53414

European-Finnish (FIN) AF: 0.000272 AC: 11 AN: 40380

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4135

European-Non Finnish (NFE) AF: 0.000162 AC: 136 AN: 840550

Other (OTH) AF: 0.0000217 AC: 1 AN: 45982

GnomAD4 genome AF: 0.000125 AC: 14 AN: 111605 Hom.: 0 Cov.: 22 AF XY: 0.000178 AC XY: 6 AN XY: 33763

African (AFR) AF: 0.0000326 AC: 1 AN: 30669

American (AMR) AF: 0.00 AC: 0 AN: 10434

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2646

East Asian (EAS) AF: 0.00 AC: 0 AN: 3551

South Asian (SAS) AF: 0.00 AC: 0 AN: 2685

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5998

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.000244 AC: 13 AN: 53206

Other (OTH) AF: 0.00 AC: 0 AN: 1497

Alfa AF: 0.000216 Hom.: 1

Bravo AF: 0.000147

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000446 AC: 3

ExAC AF: 0.000165 AC: 20

ClinVar

ClinVar submissions

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	0.067
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	17
DANN	Benign	0.90
DEOGEN2	Benign	0.11	T
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
PhyloP100		4.6
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.86	N
REVEL	Uncertain	0.33
Sift	Benign	0.32	T
Sift4G	Benign	0.48	T
Polyphen		0.0	B
Vest4		0.54
MVP		0.96
MPC		0.52
ClinPred		0.064	T
GERP RS		3.9
Varity_R		0.43
gMVP		0.71
Mutation Taster		=98/2	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: rs376230365; hg19: chrX-83319314; COSMIC: COSV99424405;