X-84065009-C-G

Variant names:

• chrX-84065009-C-G
• rs6616890
• NM_014496.5:c.2074G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014496.5(RPS6KA6):​c.2074G>C​(p.Asp692His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000915 in 1,093,453 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D692N) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: RPS6KA6 NM_014496.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.36
• Publications: 18 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: 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 (MetaRNN=0.13164985).

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.2074G>C	p.Asp692His	missense	Exon 21 of 22	NP_055311.1	Q9UK32-1
	RPS6KA6	NM_001330512.1		c.2074G>C	p.Asp692His	missense	Exon 23 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.2074G>C	p.Asp692His	missense	Exon 21 of 22	ENSP00000262752.2	Q9UK32-1
	RPS6KA6	ENST00000620340.4	TSL:5	c.2074G>C	p.Asp692His	missense	Exon 21 of 22	ENSP00000483896.1	Q9UK32-2
	RPS6KA6	ENST00000911420.1		c.2035G>C	p.Asp679His	missense	Exon 21 of 22	ENSP00000581479.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.15e-7 AC: 1 AN: 1093453 Hom.: 0 Cov.: 28 AF XY: 0.00000279 AC XY: 1 AN XY: 359011

African (AFR) AF: 0.00 AC: 0 AN: 26326

American (AMR) AF: 0.00 AC: 0 AN: 35175

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19342

East Asian (EAS) AF: 0.00 AC: 0 AN: 30143

South Asian (SAS) AF: 0.00 AC: 0 AN: 53835

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40501

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4125

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 838074

Other (OTH) AF: 0.00 AC: 0 AN: 45932

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	15
DANN	Benign	0.67
DEOGEN2	Benign	0.087	T
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PhyloP100		3.4
PrimateAI	Benign	0.30	T
PROVEAN	Benign	1.0	N
REVEL	Benign	0.079
Sift	Benign	0.35	T
Sift4G	Benign	0.31	T
Polyphen		0.0	B
Vest4		0.10
MutPred		0.25		Loss of ubiquitination at K695 (P = 0.0304)
MVP		0.33
MPC		0.61
ClinPred		0.25	T
GERP RS		-0.26
Varity_R		0.048
gMVP		0.33
Mutation Taster		=99/1	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: rs6616890; hg19: chrX-83320017;