rs34651286

Variant names:

• chr6-166412777-C-G
• rs34651286
• NM_021135.6:c.2187G>C

Your query was ambiguous. Multiple possible variants found:

• chr6-166412777-C-G
• chr6-166412777-C-T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_021135.6(RPS6KA2):​c.2187G>C​(p.Thr729Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00227 in 1,598,718 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (42 hom., cov: 35)
  • Exomes 𝑓: 0.0013 (38 hom.)
• Consequence: RPS6KA2 NM_021135.6 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.793
• 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]

LOC124901460 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 6-166412777-C-G is Benign according to our data. Variant chr6-166412777-C-G is described in ClinVar as Benign. ClinVar VariationId is 781018.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.793 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0112 (1711/152320) while in subpopulation AFR AF = 0.0386 (1605/41580). AF 95% confidence interval is 0.037. There are 42 homozygotes in GnomAd4. There are 827 alleles in the male GnomAd4 subpopulation. Median coverage is 35. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1711 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.2187G>C	p.Thr729Thr	synonymous	Exon 21 of 21	NP_066958.2
	RPS6KA2	NM_001318936.2		c.2262G>C	p.Thr754Thr	synonymous	Exon 23 of 23	NP_001305865.2	F2Z2J1
	RPS6KA2	NM_001006932.3		c.2211G>C	p.Thr737Thr	synonymous	Exon 22 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.2187G>C	p.Thr729Thr	synonymous	Exon 21 of 21	ENSP00000265678.4	Q15349-1
	RPS6KA2	ENST00000481261.6	TSL:1	c.1920G>C	p.Thr640Thr	synonymous	Exon 21 of 21	ENSP00000422484.1	B7Z3B5
	RPS6KA2	ENST00000509742.1	TSL:1	n.723G>C		non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1695 AN: 152202 Hom.: 42 Cov.: 35

Gnomad AFR AF: 0.0383

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00279 AC: 619 AN: 221642 AF XY: 0.00206

Gnomad AFR exome AF: 0.0375

Gnomad AMR exome AF: 0.00225

Gnomad ASJ exome AF: 0.000860

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000170

Gnomad OTH exome AF: 0.00203

GnomAD4 exome AF: 0.00132 AC: 1914 AN: 1446398 Hom.: 38 Cov.: 40 AF XY: 0.00115 AC XY: 828 AN XY: 717942

African (AFR) AF: 0.0408 AC: 1362 AN: 33358

American (AMR) AF: 0.00278 AC: 118 AN: 42424

Ashkenazi Jewish (ASJ) AF: 0.000624 AC: 16 AN: 25650

East Asian (EAS) AF: 0.00 AC: 0 AN: 39118

South Asian (SAS) AF: 0.000120 AC: 10 AN: 83074

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50828

Middle Eastern (MID) AF: 0.00783 AC: 45 AN: 5748

European-Non Finnish (NFE) AF: 0.000117 AC: 129 AN: 1106356

Other (OTH) AF: 0.00391 AC: 234 AN: 59842

GnomAD4 genome AF: 0.0112 AC: 1711 AN: 152320 Hom.: 42 Cov.: 35 AF XY: 0.0111 AC XY: 827 AN XY: 74482

African (AFR) AF: 0.0386 AC: 1605 AN: 41580

American (AMR) AF: 0.00457 AC: 70 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68022

Other (OTH) AF: 0.00614 AC: 13 AN: 2116

Alfa AF: 0.000767 Hom.: 0

Bravo AF: 0.0131

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.26
DANN	Benign	0.63
PhyloP100		-0.79
Mutation Taster		=93/7	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: rs34651286; hg19: chr6-166826265; COSMIC: COSV55825759;