NM_021135.6:c.1695C>T

Variant names:

• chr6-166423304-G-A
• rs147557165
• NM_021135.6:c.1695C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_021135.6(RPS6KA2):​c.1695C>T​(p.Asn565Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00374 in 1,613,970 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (19 hom.)
• Consequence: RPS6KA2 NM_021135.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.735
• Publications: 2 publications found

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

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 6-166423304-G-A is Benign according to our data. Variant chr6-166423304-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 770932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.735 with no splicing effect.
• BS2: High AC in GnomAd4 at 458 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021135.6. 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
	RPS6KA2	NM_021135.6	MANE Select	c.1695C>T	p.Asn565Asn	synonymous	Exon 17 of 21	NP_066958.2
	RPS6KA2	NM_001318936.2		c.1770C>T	p.Asn590Asn	synonymous	Exon 19 of 23	NP_001305865.2	F2Z2J1
	RPS6KA2	NM_001006932.3		c.1719C>T	p.Asn573Asn	synonymous	Exon 18 of 22	NP_001006933.3	Q15349-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS6KA2	ENST00000265678.9	TSL:1 MANE Select	c.1695C>T	p.Asn565Asn	synonymous	Exon 17 of 21	ENSP00000265678.4	Q15349-1
	RPS6KA2	ENST00000481261.6	TSL:1	c.1428C>T	p.Asn476Asn	synonymous	Exon 17 of 21	ENSP00000422484.1	B7Z3B5
	RPS6KA2	ENST00000509742.1	TSL:1	n.231C>T		non_coding_transcript_exon	Exon 2 of 6

Frequencies

GnomAD3 genomes AF: 0.00301 AC: 458 AN: 152224 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000699

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00451

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00469

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00300 AC: 754 AN: 251154 AF XY: 0.00309

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00391

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000278

Gnomad NFE exome AF: 0.00432

Gnomad OTH exome AF: 0.00685

GnomAD4 exome AF: 0.00381 AC: 5572 AN: 1461628 Hom.: 19 Cov.: 31 AF XY: 0.00383 AC XY: 2783 AN XY: 727110

African (AFR) AF: 0.000508 AC: 17 AN: 33470

American (AMR) AF: 0.00369 AC: 165 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00222 AC: 58 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00189 AC: 163 AN: 86254

European-Finnish (FIN) AF: 0.000244 AC: 13 AN: 53308

Middle Eastern (MID) AF: 0.00902 AC: 52 AN: 5764

European-Non Finnish (NFE) AF: 0.00439 AC: 4882 AN: 1111914

Other (OTH) AF: 0.00366 AC: 221 AN: 60378

GnomAD4 genome AF: 0.00301 AC: 458 AN: 152342 Hom.: 1 Cov.: 32 AF XY: 0.00291 AC XY: 217 AN XY: 74488

African (AFR) AF: 0.000697 AC: 29 AN: 41588

American (AMR) AF: 0.00451 AC: 69 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4832

European-Finnish (FIN) AF: 0.000753 AC: 8 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00469 AC: 319 AN: 68024

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00393 Hom.: 2

Bravo AF: 0.00322

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00431

EpiControl AF: 0.00545

ClinVar

ClinVar submissions

Significance: Benign/Likely 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
BayesDel_noAF	Benign	-0.42
CADD	Benign	3.9
DANN	Benign	0.84
PhyloP100		-0.73
Mutation Taster		=100/0	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: rs147557165; hg19: chr6-166836792; COSMIC: COSV55815251;