X-84065009-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014496.5(RPS6KA6):​c.2074G>A​(p.Asp692Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0608 in 1,203,882 control chromosomes in the GnomAD database, including 2,128 homozygotes. There are 24,300 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.062 (229 hom., 1968 hem., cov: 22)
  • Exomes 𝑓: 0.061 (1899 hom. 22332 hem.)
• Consequence: RPS6KA6 NM_014496.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012203455).
• BP6: Variant X-84065009-C-T is Benign according to our data. Variant chrX-84065009-C-T is described in ClinVar as Benign. ClinVar VariationId is 1288726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.19 is higher than 0.05.

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>A	p.Asp692Asn	missense	Exon 21 of 22	NP_055311.1	Q9UK32-1
	RPS6KA6	NM_001330512.1		c.2074G>A	p.Asp692Asn	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>A	p.Asp692Asn	missense	Exon 21 of 22	ENSP00000262752.2	Q9UK32-1
	RPS6KA6	ENST00000620340.4	TSL:5	c.2074G>A	p.Asp692Asn	missense	Exon 21 of 22	ENSP00000483896.1	Q9UK32-2
	RPS6KA6	ENST00000911420.1		c.2035G>A	p.Asp679Asn	missense	Exon 21 of 22	ENSP00000581479.1

Frequencies

GnomAD3 genomes AF: 0.0616 AC: 6810 AN: 110615 Hom.: 229 Cov.: 22

Gnomad AFR AF: 0.0483

Gnomad AMI AF: 0.235

Gnomad AMR AF: 0.0980

Gnomad ASJ AF: 0.0699

Gnomad EAS AF: 0.203

Gnomad SAS AF: 0.0751

Gnomad FIN AF: 0.0286

Gnomad MID AF: 0.0921

Gnomad NFE AF: 0.0527

Gnomad OTH AF: 0.0698

GnomAD2 exomes AF: 0.0793 AC: 14518 AN: 183055 AF XY: 0.0757

Gnomad AFR exome AF: 0.0487

Gnomad AMR exome AF: 0.121

Gnomad ASJ exome AF: 0.0701

Gnomad EAS exome AF: 0.222

Gnomad FIN exome AF: 0.0363

Gnomad NFE exome AF: 0.0539

Gnomad OTH exome AF: 0.0733

GnomAD4 exome AF: 0.0607 AC: 66389 AN: 1093213 Hom.: 1899 Cov.: 28 AF XY: 0.0622 AC XY: 22332 AN XY: 359001

African (AFR) AF: 0.0486 AC: 1280 AN: 26320

American (AMR) AF: 0.124 AC: 4354 AN: 35173

Ashkenazi Jewish (ASJ) AF: 0.0704 AC: 1362 AN: 19340

East Asian (EAS) AF: 0.252 AC: 7609 AN: 30138

South Asian (SAS) AF: 0.0918 AC: 4944 AN: 53827

European-Finnish (FIN) AF: 0.0349 AC: 1415 AN: 40496

Middle Eastern (MID) AF: 0.104 AC: 429 AN: 4125

European-Non Finnish (NFE) AF: 0.0501 AC: 41974 AN: 837866

Other (OTH) AF: 0.0658 AC: 3022 AN: 45928

GnomAD4 genome AF: 0.0617 AC: 6831 AN: 110669 Hom.: 229 Cov.: 22 AF XY: 0.0598 AC XY: 1968 AN XY: 32937

African (AFR) AF: 0.0488 AC: 1487 AN: 30454

American (AMR) AF: 0.0981 AC: 1020 AN: 10401

Ashkenazi Jewish (ASJ) AF: 0.0699 AC: 184 AN: 2631

East Asian (EAS) AF: 0.203 AC: 707 AN: 3487

South Asian (SAS) AF: 0.0761 AC: 195 AN: 2564

European-Finnish (FIN) AF: 0.0286 AC: 167 AN: 5844

Middle Eastern (MID) AF: 0.100 AC: 22 AN: 219

European-Non Finnish (NFE) AF: 0.0527 AC: 2788 AN: 52896

Other (OTH) AF: 0.0695 AC: 105 AN: 1510

Alfa AF: 0.0619 Hom.: 4271

Bravo AF: 0.0710

TwinsUK AF: 0.0526 AC: 195

ALSPAC AF: 0.0523 AC: 151

ESP6500AA AF: 0.0498 AC: 191

ESP6500EA AF: 0.0528 AC: 355

ExAC AF: 0.0773 AC: 9383

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.91	T
BayesDel_noAF	Benign	-0.94
CADD	Benign	15
DANN	Benign	0.76
DEOGEN2	Benign	0.061	T
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
PhyloP100		3.4
PrimateAI	Benign	0.30	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.092
Sift	Benign	0.93	T
Sift4G	Benign	0.66	T
Polyphen		0.0	B
Vest4		0.093
MPC		0.51
ClinPred		0.013	T
GERP RS		-0.26
Varity_R		0.041
gMVP		0.19
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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; COSMIC: COSV53117092;